DAta | National Center for Advancing Translational Sciences

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3395	Modeling the Female Reproductive Tract in 3-D: The Birth of EVATAR™	April 2017 Update Science fiction and gaming enthusiasts are familiar with the concept of an avatar, the digital character a user creates to navigate a virtual world. Now, NIH-funded researchers are turning science fiction into scientific reality by building one. EVATAR™ is a miniaturized 3-D representation of the female reproductive tract and liver on a handheld, interconnected platform. The team of scientists from Northwestern University, Charles Stark Draper Laboratory and the University of Illinois at Chicago (UIC) is designing the model for use in drug testing and to study the basic biology of female reproduction. Too often, laboratory and animal tests used by scientists in the early phases of research fail to predict a therapy’s effectiveness or potential side effects in humans. Use of inaccurate models can result in many years and millions of dollars being wasted while patients wait for effective treatments. Researchers need scientifically valid alternatives for predicting treatment effectiveness and safety. Another issue is consideration of sex as a biological variable. Although women now comprise roughly half the participants in NIH-funded clinical trials, the same is not true for preclinical research. More often than not, preclinical research conducted to date has involved mostly male-derived cells and male animals. These practices have resulted in a lack of information about female physiology and women’s health. To address these and other drug development challenges, NCATS, along with the Defense Advanced Research Projects Agency and the Food and Drug Administration, developed the Tissue Chip for Drug Screening program. Program funding is used to support scientists developing 3-D platforms with living human tissues and cells, called tissue chips or organs-on-chips. These devices are designed as accurate models of the structure and function of human organs and systems, such as the lung, liver, heart and, in this case, female reproductive tract. A Team Effort The EVATAR™ team at Northwestern University. (Northwestern University Photo) Led by Northwestern University principal investigator and ovarian biology researcher Teresa Woodruff, Ph.D., the EVATAR™ team first came together in 2012 with funding from NIH’s first round of Tissue Chip program awards. At the time, each team member was working separately on 3-D models of different female reproductive organs: Woodruff on the ovaries; Joanna Burdette, Ph.D. (UIC), on the fallopian tubes; Julie Kim, Ph.D. (Northwestern), on the uterus; and Spiro Getsios, Ph.D. (Northwestern), on the cervix and vagina. Beth Sefton, Ph.D., at Northwestern, coordinates the work on EVATAR™ and ensures that the system and the investigators are all communicating in order to speed the pace and quality of the research. “We’d each had a longstanding interest in developing 3-D organ models, and this opportunity enabled us to bridge together what we were all doing individually,” Burdette said. “For the first time, as a collaborative team, we attempted to create a 3-D model of the entire female reproductive tract.” The Northwestern team and their partners from the Draper laboratory, Jonathan Coppeta, Ph.D., and Jeff Borenstein, Ph.D., have produced a device that enables the female reproductive tissue to interact over periods of a month or more, much like they do in the human body. This advance solved a major technical challenge in the field: enabling organ models to communicate with each other via secreted factors, including hormones, to more closely resemble how they work together in the body. The NCATS project, which was co-funded by the National Institute of Environmental Health Sciences, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the NIH Office of Research on Women’s Health (ORWH), and the NIH Common Fund, exemplifies the power of cooperation among NIH Institutes, Centers and Offices. “This work is a remarkable advance for understanding female biology, and it will fill an important gap,” said Janine A. Clayton, M.D., ORWH director. “It’s a perfect example of how considering sex as a biological variable can help us develop individualized treatments and learn more about how females may metabolize drugs differently from males.” Building EVATAR™ From puberty until menopause, the female reproductive system is capable of an amazing feat: growing a new human being. The ovaries, fallopian tubes, uterus, cervix and vagina use hormones to communicate and regulate each other. In premenopausal women, for example, every month a cascade of hormones fuels the growth and release of an egg from the ovaries; this process then triggers the other organs to prepare the fallopian tubes as the site of fertilization and the uterus for implantation of an embryo. The vagina and cervix act as the first line of defense for the female reproductive tract, protecting it from invaders that could cause infection. Although not part of the female reproductive system, the liver serves an important role in metabolizing reproductive hormones and regulating their effects, as well as the effects of therapeutics such as chemotherapy drugs and endocrine disruptors. These hormones also circulate through the body and affect non-reproductive processes, such as bone and heart functions. Studying the tissues as individual units limits scientists’ ability to learn how these organs work as a system. But until now, such a system did not exist. Since 2012, the EVATAR™ group has been refining the individual organ components and building the integrated 3-D platform, which has three layers. The top layer contains multiple components that individually support the cells of each of the five organs. The bottom two layers hold the miniaturized pumps and tubes (called microfluidics) that mimic the human body environment, carrying liquids and hormones through each of the tissues. The model organs can be inserted or removed from the platform base as needed. “We currently are working to ensure that all of the microfluidics and hormones on the platform are behaving the way we expect,” Woodruff explained. Soon, the group will add each of the tissue types and hormones and test the entire system for the first time. The hormone fluctuations and behavior of the cells are designed to mimic a woman’s 28-day reproductive cycle. The Future of EVATAR™ By more closely representing a woman’s reproductive biology and cycling hormones, EVATAR™ could help researchers overcome the limits of understanding female physiology using animals or cells grown in a lab. Woodruff’s group, for example, plans to use EVATAR™ to better understand the basic hormonal and cellular functioning of the reproductive tract. The platform also could help scientists understand the various cancers, sexually transmitted infections and benign tumors that can affect female reproductive organs. In addition, researchers will be able to use EVATAR™ to predict whether a candidate drug, vaccine or biologic agent is safe or toxic in humans in a faster and more cost-effective way than is possible with current methods. The liver component will be able to process drugs, and since reproductive hormones affect how the liver works, the platform could help scientists understand how a drug will affect women with different hormone levels. The ultimate goal is to integrate EVATAR™ with the Tissue Chip program’s other organs-on-chips to make an integrated model of a human body on a chip, enabling scientists to test the varying effects of a drug across the entire body before testing it in people. “All of our organs are in constant dynamic communication with each other, but we’ve never been able to model that in a dish,” Woodruff said. “We’re really excited about this opportunity. For us, it’s like landing on the moon.” Explore more about EVATAR™ and other tissue chips being developed via Chip, an online interactive model of the innovative developments from the NCATS-supported Tissue Chip for Drug Screening program. Watch the Tissue Chip for Drug Screening video to learn more about the program. April 2017 Update NCATS-supported scientists at Northwestern University were part of a team of researchers who recently reported on an advance relevant to the August 2015 Evatar story above. As published in Nature Communications and announced by Northwestern, the team created a miniature, working female reproductive system consisting of 3-D models of five reproductive organs: ovaries, fallopian tubes, the uterus, cervix and vagina, in addition to liver. The models communicate by way of secreted substances, including hormones, to mimic how they work together in a woman’s body in processes such as the 28-day reproductive cycle. Posted August 2015
3385	Anton Simeonov Named NCATS Scientific Director	On Aug. 9, 2015, Anton Simeonov, Ph.D.,became the scientific director at NCATS, where he has been serving as the acting scientific director since Jan. 6, 2015. Simeonov will lead the Center’s Division of Preclinical Innovation (DPI), which develops, demonstrates and disseminates new technologies that make the early stages of translational research more predictive and efficient. Together with collaborators worldwide, NCATS DPI scientists “de-risk” novel targets and therapeutic development projects, making them more attractive for commercial investment. “Anton brings with him more than 17 years of translational experience in the public and private sectors, including development of novel detection chemistries and techniques, assays and devices for diagnostics, assay miniaturization, and novel catalytic approaches to screening and therapeutics development,” said NCATS Director Christopher P. Austin, M.D. “Adding to this his collaborative spirit, relentless focus on innovation and vision for achieving NCATS translational science goals, he is the perfect fit to lead NCATS’ preclinical science initiatives.” “I believe strongly in the NCATS mission to address translational research problems through innovative technologies and solutions that all researchers can use,” Simeonov said. “I look forward to continuing my work with such a talented group of researchers who share the NCATS goal of getting more treatments to more patients more quickly.” Simeonov first came to NIH in 2004 to work for the National Human Genome Research Institute (NHGRI) as group leader — and eventually branch chief — for bioorganic chemistry and assay technologies in the NIH Chemical Genomics Center, which is now the NCATS Chemical Genomics Center. Prior to joining NIH, he was a senior scientist at Caliper Life Sciences, a leading developer of microfluidic technologies, where he was responsible for both basic research on novel assay methodologies and development of microfluidic products for research and clinical diagnostics. Simeonov is the author of more than 120 peer-reviewed scientific publications and the inventor behind 15 patents, and he has been recognized with multiple awards from NIH, NCATS and NHGRI directors. He received a B.A. in chemistry from Concordia College and a Ph.D. in bioorganic chemistry from the University of Southern California, followed by a postdoctoral fellowship at The Scripps Research Institute with Richard Lerner, M.D., and Kim Janda, Ph.D. For more information, visit Simeonov’s Staff Profile page or watch the new video Inside the NCATS Laboratories. Posted August 2015
3336	CTSA Program PAR Frequently Asked Questions	Questions and answers for PAR-15-304 are applicable to PAR-18-464. Budget and Funding Are subaward recipients permitted to charge indirect costs for pilots and clinical studies? Are there any restrictions on indirect costs applied to pilots and clinical studies? Are CTSA Program institutions responding to PAR 15-304 being asked to publish a comprehensive list of clinical charges with cost-center based application of the DHHS Rate Agreement? Or, are they instead supposed to supply a list of charges only for research (i.e., nonclinical) items that might be associated with NIH multisite clinical trials? Based on the funding opportunity announcement (FOA) guidance, how much funding is available to a specific applicant? Based on a current award of $7,219,327 (total costs), which is more than $3 million plus $2,165,798, would an institution be eligible for the phase-in plan? If so, how are the direct cost numbers determined for years one to three? Are the direct costs of subcontracts for participating institutions excluded from the direct cost cap of $7.5 million? Certain sections have direct cost caps based on the size of the CTSA Program hub. Is there flexibility to re-budget between these sections such that the overall total is at the $7.5 million cap? Are no-cost extensions permitted under the CTSA Program? Can a no-cost extension be requested on all linked awards including the K and T? Is there any guidance on which Facilities and Administration rates to apply? What rate should be applied on the U54? Should the standard 8 percent be applied to the KL2 and the TL1? Will any escalations to salary or fringe benefits be awarded? Or should both be static across all five years of the proposed budget? What is the appropriate reference to calculate the CTSA Program budget for the U and K components of PAR 15-304? When is the NIH direct-cost, institutional NIH funding link (prior FY award data table) referenced in the PAR updated to reflect the prior fiscal year? Application Information Are websites and website URLs allowed in the narrative sections of an application to CTSA Program PAR-15-304? Should current and potential grantees submit applications as “renewal,” “new” or “resubmission?” Are current grantees required to submit their progress reports with new applications? Can a letter of support mention more than one component (i.e., Informatics and Community and Collaboration) and be attached under each component’s “Letters of Support” section? Can the “Pilot Translational and Clinical Studies (PTC)” under “Translational Endeavors” be completely supported by the institution? How should “additional support” be presented in the application, and how is it different from cost sharing? Can additional support be quantified? PAR-15-304 indicates that travel to support up to five participants to attend the annual CTSA Program Steering Committee meeting is allowed and should be budgeted in the Administrative Core budget. In addition, travel for the TL1 Project Lead is allowed on the Administrative Core budget. Is this the only travel funding allowed on the UL1 portion of the U54? As an existing CTSA Program hub submitting a “new” application, may we include a publication list? Does the 30-letter limit for letters of support apply to all sections (i.e., U + K + T = 30 total)? If human subjects (HS) and vertebrate animal (VA) subjects are used in two components, do we need to attach a description of how HS/VA research is handled for the entire application in the Overall Component or upload attachments specifically under the two components conducting HS/VA research? What is the appropriate clinical trial designation, time frame and activation parameter to include in the NIH-Defined Phase III Clinical Trial table? The previous RFAs for the CTSA Program grant mandated 20 percent effort for the principal investigator (PI) and co-directors. This mandate is not listed in the current FOA. Do the PI and co-directors still need to account for a minimum of 20 percent effort? What allowable materials can applicants place in the appendix of the U54 application? Are the “Specific Aims” (one-page limit) in addition to and separate from the “Research Plan” (six-page limit)? For “Optional Functions,” the page limitations table lists six pages as the limit for this component. If two optional functions are being proposed, can each function be six pages long (12 pages total), or do they need to be six pages total? Also, should each function be uploaded separately in ASSIST with a distinct title to differentiate between the two optional functions? What is the difference between a renewal and a resubmission application? If an application in response to RFA-TR-14-009 was unsuccessful and will be submitted again, is it required to address the previous review comments? What is meant by "CTSA Program hubs with more than 16 months of remaining support at the date of submission are not eligible to submit an application"? Please provide an example. Are the page limits specified in this FOA tied to the amount of funds being requested, and are page limits different for those institutions that already have CTSA Program grants? Which biographical sketches should be included in the application? Do applicants need to name project leads for each FOA component as well as for each function? What application types are allowed under PAR-18-464 ? NEW (Feb. 2018): What is the page limit for the U/K/T CTSA Program progress reports for renewal applications? NEW (Feb. 2018): Can NCATS confirm that “Equipment” is a required attachment for PAR-18-464? NEW (Feb. 2018): What format should be used in preparing the multicomponent U54 application? NEW (April 2018): Can an institution commit to more than one CTSA application as a participating partner institution? Training and Career Development Are the recommended number of scholars referenced in PAR 15-304 indicated for the entire grant period? The FOA states: "The recommended number of scholars to budget for in the application is four for small hubs (total anticipated CTSA Program award <$4.5M DC), six for medium hubs (total anticipated CTSA Program award $4.5M-$6M DC), and nine for large hubs (total anticipated CTSA Program award >$6M-$7.5M DC)." Can long-term trainee appointments between pre- and post-doctoral applicants change each year, depending on the pool of applicants keeping the same number of approved slots? Is there a limit on the number of mentors that may be submitted under the Institutional Career Development Core and the Training Core (as applicable)? When budgeting for the KL2 program, can the institution supplement the NIH salary up to a level that is consistent with the institution’s salary scale? Is budgeting salary support for the Project Lead and staff to support the program allowed as part of the KL2 budget? Is budgeting salary support for the Project Lead to support the program allowed as part of the TL1 budget? The budget section of the Training Core (TL) component indicates that in addition to stipends for trainees, training-related expenses also can be requested. May “training-related expenses” include salary and travel support for Training Core Leader(s) and other staff needed to administer the program? Does the $120,000 per scholar salary support cap include benefits? What training data tables are required for the T and K components? NEW (Feb. 2018): The descriptive guidance for Scholar Candidates* no longer requests information on the candidate pool, recruitment, nomination and selection. Is this information no longer required? For More Information What if I have additional questions? Budget and Funding Are subaward recipients permitted to charge indirect costs for pilots and clinical studies? Yes; however, the applicant institution must establish consortium agreements consistent with the applicable government-wide cost principles and NIH cost policies. Are there any restrictions on indirect costs applied to pilots and clinical studies? Applicant institutions must use an approved, federally recognized indirect cost rate negotiated between the subaward recipient and the federal government. If no such rate exists, the applicant institution must use either a rate it has negotiated with the subaward recipient, or a de minimis indirect cost rate of 10 percent of modified total direct costs if the subaward recipient has never received a negotiated indirect cost rate from the federal government. Are CTSA Program institutions responding to PAR 15-304 being asked to publish a comprehensive list of clinical charges with cost-center based application of the DHHS Rate Agreement? Or, are they instead supposed to supply a list of charges only for research (i.e., nonclinical) items that might be associated with NIH multisite clinical trials? No. CTSA Program institutions responding to PAR-15-304 are not being asked to publish a comprehensive list of clinical charges with cost-center based application of the DHHS Rate Agreement. Although CTSA Program institutions are asked to maintain a transparent cost structure for translational research projects supported by the CTSA Program, the DHHS rate agreement may or may not be applicable to this cost structure depending on your organization and the activities supported. The guidance in the PAR-15-304 concerning institutional letters of support requests assurance that the applicant institution will work under a central IRB, use master subcontract agreements/trial agreements, and will work under a transparent cost structure for research items associated with multisite clinical trials (e.g., per patient costs) supported by the CTSA Program. The negotiated patient care rate agreement between a CTSA Program institution and the DHHS is a separate fiduciary document used to determine reimbursement rates for services performed for research purposes using federal funds. Based on the funding opportunity announcement (FOA) guidance, how much funding is available to a specific applicant? Based on a current award of $7,219,327 (total costs), which is more than $3 million plus $2,165,798, would an institution be eligible for the phase-in plan? If so, how are the direct cost numbers determined for years one to three? In determining the appropriate budget calculation, grantees should first determine any and all partner organizations associated with the hub institution. Secondly, use the table provided (Excel - 113KB) to determine the maximum budget (2.5 percent of NIH direct costs) that can be requested for the UL1 and KL2 awards. The most recent facilities and administrative (F&A) rate should be applied to the direct costs on the UL1, and the F&A rate of 8 percent should be applied to the direct costs on the KL2 to determine the total anticipated award for the application. If the total anticipated award for the new application is less than the prior CTSA Program award for U and K total costs (excluding supplements and carryover) by more than 30 percent, the phase-in plan should be used. Depending on the amount of discrepancy between the prior CTSA Program award and the current budget calculated in response to PAR-15-304, it may be possible to reach the maximum cost within the first two years of the grant by applying the phase-in plan. Are the direct costs of subcontracts for participating institutions excluded from the direct cost cap of $7.5 million? No, all direct costs for the parent grant and any sub-award agreements are included in the direct cost cap. Sub-award facilities and administrative costs are excluded from the direct cost cap. Certain sections have direct cost caps based on the size of the CTSA Program hub. Is there flexibility to re-budget between these sections such that the overall total is at the $7.5 million cap? There is flexibility. The amounts listed in this funding opportunity are “suggested,” and the PAR states, “The budget will depend on the development needs for each hub to reach the strategic goals.” Are no-cost extensions permitted under the CTSA Program? Can a no-cost extension be requested on all linked awards including the K and T? Yes, all NIH grants are subject to the NIH Grants Policy Statement, which permits grantees to extend the final budget period of the previously approved project period once for up to 12 months beyond the original completion date shown in the Notice of Award. No additional funds are required to be obligated by the NIH awarding Institute or Center, and the originally approved scope of work will not change. No new scholars or trainees can be appointed in an extension period. Is there any guidance on which Facilities and Administration rates to apply? What rate should be applied on the U54? Should the standard 8 percent be applied to the KL2 and the TL1? Check with your Office of Sponsored Research for guidance on your institutional facilities and administration rate. For the KL2 and TL1 components, recipients will receive F&A costs at 8 percent of modified total direct costs. Will any escalations to salary or fringe benefits be awarded? Or should both be static across all five years of the proposed budget? No, NCATS will not award inflation-driven increases to salary or fringe benefits in subsequent budget years. What is the appropriate reference to determine how much support may be requested in response to this PAR? In compliance with NIH policy, the PAR-15-304 now has to refer to direct cost rather than total cost. The amounts up to which support may be requested are in the same range as they were in RFA-TR-14-009, but now are expressed in direct cost. The statement provided in the "Administrative Core" budget section along with the table referenced therein refers to direct cost. What is the appropriate reference to calculate the CTSA Program budget for the U and K components of PAR 15-304? Applicants must use the direct-cost, institutional NIH funding link provided in the PAR under the Budget (Administrative Core) section to calculate the budget for the U and K components. Direct-cost support is limited to 2.5 percent of the entire NIH direct-cost funding to the institution in the fiscal year prior to the time of application. When is the NIH direct-cost, institutional NIH funding link (prior FY award data table) referenced in the PAR updated to reflect the prior fiscal year? Due to NIH requirements for end-of-year closing, the link generally is updated in February each year. This means that applications submitted for the January 25 receipt date will not be able to use the data from the most recent fiscal year. For example, applications submitted for the January 2018 receipt date will use the link provided in the PAR that will populate data from FY 2016. Any updates to the NIH funding link will be made directly to the PAR. Back to top Application Information Are websites and website URLs allowed in the narrative sections of an application to CTSA Program PAR-15-304? According to the PHS SF424 guidance, “Unless otherwise specified in an NIH solicitation, internet website addresses (URLs) may not be used to provide information necessary to the review because reviewers are under no obligation to view the internet sites. Moreover, reviewers are cautioned that they should not directly access an internet site as it could compromise their anonymity. Should current and potential grantees submit applications as “renewal,” “new” or “resubmission?” The PAR allows renewal applications only from institutions that were funded under RFA-TR-14-009 or the current PAR-15-304. Applications from institutions that currently have a CTSA Program award funded under any other FOA will be considered as new applications. Are current grantees required to submit their progress reports with new applications? For “new” applications, reviewers will not have access to progress reports, and the following content is not allowed anywhere in a new application or its associated components (e.g., the appendix, letters of support, other attachments): Introduction page(s) to respond to critiques from a previous review Mention of previous overall or criterion scores Mention of comments made by previous reviewers Responses to a prior review Mention of how the application or project has been modified since its last submission Marks in the application to indicate where the application has been modified since its last submission Progress Report Progress Report Publication List Can a letter of support mention more than one component (i.e., Informatics and Community and Collaboration) and be attached under each component’s “Letters of Support” section? General letters of support for the CTSA Program should be submitted with the Overall component in ASSIST (limit of 30 letters). Letters of support that specifically mention individual components (i.e., Informatics and Community and Collaboration) can be submitted under each of the components mentioned. Note that a letter of support that mentions all components by name should be considered a general letter of support and included once, with the Overall section only. Can the “Pilot Translational and Clinical Studies (PTC)” under “Translational Endeavors” be completely supported by the institution? No. Translational Endeavors is a required component of the U54 application. If the institution opts to utilize other institutional resources to support a larger entity than is required by the FOA, the additional funding support will be considered voluntary cost sharing. Awarded grantees must ensure that voluntary cost sharing commitments are appropriately tracked, monitored and reported. How should “additional support” be presented in the application, and how is it different from cost sharing? Can additional support be quantified? The current FOA does not require cost sharing. Additional support provided by the grantee and partner institutions should be described in a non-quantitative format in the letters of support. Institutional commitment also can be presented in a non-quantitative format in the Resources section of the application. Voluntary institutional commitment should not be reported in the application Budget Forms or Budget Justification. Any quantitative, itemized (voluntary) institutional commitment reported in the application will be considered cost sharing. Cost sharing is not permitted on the TL1 and KL2 core components. PAR-15-304 indicates that travel to support up to five participants to attend the annual CTSA Program Steering Committee meeting is allowed and should be budgeted in the Administrative Core budget. In addition, travel for the TL1 Project Lead is allowed on the Administrative Core budget. Is this the only travel funding allowed on the UL1 portion of the U54? The expectation is that administrative operations will be streamlined so that the direct cost for administration does not exceed 10 percent of the total UL1 direct costs. Therefore, discretion should be exercised in determining travel allowances beyond what is specified under the Administrative Core budget and supported with a strong justification. As an existing CTSA Program hub submitting a “new” application, may we include a publication list? Yes, you may include publications within the page limit restrictions for each core component. According to the PAR, publications are requested particularly in the Overall Core and under the program plan for the Institutional Career Development Core and the Training Core. However, you must follow the page limit guidelines for submitting publications. The publication list submitted with your institution's Research Performance Progress Report is not permitted. Does the 30-letter limit for letters of support apply to all sections (i.e., U + K + T = 30 total)? No, each core component of the U54 application has a separate upload in ASSIST for letters of support (including the K and T cores). Only the Overall component limits the number of general letters of support as defined in the PAR to 30 letters. If human subjects (HS) and vertebrate animal (VA) subjects are used in two components, do we need to attach a description of how HS/VA research is handled for the entire application in the Overall Component or upload attachments specifically under the two components conducting HS/VA research? Under each core component, applicants will need to answer the questions, “Are human subjects involved?” and “Are vertebrate animals used?” in the R&R Other Project Information form of ASSIST. If an applicant answers “Yes” to either question, he/she must attach a component-specific response. If neither HS nor VA are used in a specific component, answer “No” to the questions as applicable, and there are no accompanying attachments required for those components. Additionally, if HS or VA involvement is endorsed in any component of the entire U54 application, the applicant should answer “Yes” to the questions, “Are human subjects involved?” and “Are vertebrate animals used?” in the R&R Other Project Information form under the Overall component. In this case, an attachment should be uploaded under the Overall component describing the institutional policies on protections for HS and VA welfare for the entire application. For the K and T components, please follow the detailed guidance in SF424 (R&R) Application Guide Training Instructions. What is the appropriate clinical trial designation, time frame, and activation parameter to include in the NIH-Defined Phase III Clinical Trial table? The NIH definition of a Phase III Clinical Trial, as pertains to the review of applications submitted to the NIH is referenced under the glossary of terms. The guidance provided in the PAR concerning the time frame for reporting “trials activated “ is the first half of the calendar year (January – June) prior to the application submission date. Reporting metrics for the table are not limited to NIH-funded research. Therefore, you may use your discretion to include clinical affiliates within the six-page limit designated for the Network Capacity Core. The site activation parameter for investigator-initiated, single-site studies is the date of IRB approval and for multisite studies, it is the date when the site is activated by the sponsor. The previous RFAs for the CTSA Program grant mandated 20 percent effort for the principal investigator (PI) and co-directors. This mandate is not listed in the current FOA. Do the PI and co-directors still need to account for a minimum of 20 percent effort? No. The equivalent of two months effort is the official guidance referenced in the PAR under Section III. Eligibility Information: “The CTSA Program PDs/PIs are each expected to commit at least two months and preferably three to six months effort to the award.” What allowable materials can applicants place in the appendix of the U54 application? Effective Jan. 25, 2018, the NIH/AHRQ/NIOSH policy eliminates most former allowable appendix material for applications. Are the “Specific Aims” (one-page limit) in addition to and separate from the “Research Plan” (six-page limit)? According to PHS SF424 instructions, the “Specific Aims” section is a separate (one-page) document not included with the “Research Plan.” The Specific Aims page requires a separate upload into the NIH ASSIST system. Unless specified otherwise in PAR 15-304, the page limits should follow those referenced by PHS SF424. For “Optional Functions,” the page limitations table lists six pages as the limit for this component. If two optional functions are being proposed, can each function be six pages long (12 pages total), or do they need to be six pages total? Also, should each function be uploaded separately in ASSIST with a distinct title to differentiate between the two optional functions? Up to two optional functions may be included in the “Optional Functions” Core. Each proposed function is allowed six pages for the research plan. Each research plan should be uploaded separately in the NIH ASSIST system, with a distinct title to differentiate between the two optional functions. What is the difference between a renewal and a resubmission application? A renewal applicant seeks support for a current or recent previously-funded program. A resubmission application is an amended version of a previously submitted application. If an application in response to RFA-TR-14-009 was unsuccessful and will be submitted again, is it required to address the previous review comments? An applicant who applied under RFA-TR-14-009 can choose to submit his/her application as a resubmission or as a new application. If the applicant chooses to resubmit, reviewers will have the previous summary statement, and the applicant will need to address the previous comments and include an introduction. If the applicant chooses to submit an application as a new submission, reviewers will not have access to the previous summary statement, and he/she is not allowed to address previous comments from reviewers or include an introduction. Note that the following content is not allowed anywhere in a new application or its associated components (e.g., the appendix, letters of support, other attachments): Introduction page(s) to respond to critiques from a previous review Mention of previous overall or criterion scores or percentile Mention of comments made by previous reviewers Responses to a prior review Mention of how the application or project has been modified since its last submission Marks in the application to indicate where the application has been modified since its last submission Progress Report Progress Report Publication List See NOT-OD-15-059 and NOT-OD-15-095 for additional details. What is meant by "CTSA Program hubs with more than 16 months of remaining support at the date of submission are not eligible to submit an application"? Please provide an example. If you have a CTSA Program grant with a May 31, 2018, project period end date, the earliest date an applicant could submit an application in response to this FOA would be Jan. 28, 2017. Are the page limits specified in this FOA tied to the amount of funds being requested, and are page limits different for those institutions that already have CTSA Program grants? The page limits specified in this FOA are the same for all applicants, regardless of the amount of funds being requested and whether the applicant already has a CTSA Program grant. Which biographical sketches should be included in the application? Applicants should include biographical sketches only for professional staff named in the application who contribute to the program in substantive and measurable ways. Do applicants need to name project leads for each FOA component as well as for each function? A project lead must be named for each component (e.g., Research Methods); however, a project lead does not need to be named for each function (e.g., Biostatistics, Epidemiology and Research Design). What application types are allowed under PAR-18-464 ? The current FOA allows the following types of applications: New Renewals for RFA-TR-14-009 Resubmissions for RFA-TR-14-009, PAR-15-304 and this FOA. Applications from institutions that currently have a CTSA Program award will be considered as new applications unless: They are resubmissions or renewals of applications submitted to RFA-TR-14-009, or They are resubmissions from PAR-15-304 and this FOA. The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types. What is the page limit for the U/K/T CTSA Program progress reports for renewal applications? Progress Report for Renewal and Revision Applications: Note that the Progress Report falls within the Research Strategy and is therefore included in the page limits for the Research Strategy. For renewal/revision applications, provide a Progress Report. Provide the beginning and ending dates for the period covered since the last competitive review. In the Progress Report, grantees should: Summarize the specific aims of the previous project period and the importance of the findings, and emphasize the progress made toward their achievement. Explain any significant changes to the specific aims and any new directions, including changes resulting from significant budget reductions. Discuss previous participant enrollment (e.g., recruitment, retention, inclusion of women, minorities, children, etc.) for any studies meeting the NIH definition for clinical research. Use the Progress Report section to discuss, but not duplicate information collected elsewhere in the application. Do not include a list of publications, patents or other printed materials in the Progress Report. That information will be included in the "Progress Report Publication List" attachment. Can NCATS confirm that “Equipment” is a required attachment for PAR-18-464? The “Equipment” attachment is required. Guidance concerning the format and content are referenced in Forms E SF424. Format: Attach this information as a PDF file. Content: List major items of equipment already available for this project and, if appropriate, identify the equipment's location and pertinent capabilities. What format should be used in preparing the multicomponent U54 application? The current SF424 Instructions clearly state: “Organize the Research Strategy in the specified order, and use the instructions provided unless otherwise specified in the FOA.” In other words, instructions in the FOA supersede the more general instructions in the SF424. Applicants should follow the PAR-18-464 detailed instructions for preparing an application as referenced under Research Strategy e.g., Overall Component. Guidance categories include Vision and Strategic Goals, Track Record in Translational and Clinical Research, Integration of Health Care and Research, and Workforce Diversity. Can an institution commit to more than one CTSA application as a participating partner institution? No, the proposed CTSA partnership should be a substantive and unique arrangement, leveraging stakeholders across the translational research spectrum. Additionally, there are budgetary constraints as noted in PAR-18-464. “The maximum total amount that can be requested per year for the U and K awards” is based on total institutional NIH direct costs funding of a single applicant institution, plus the possibility of one or more participating partner institutions. Therefore, if an institution is already a “participating partner institution” with a funded CTSA hub, the institution cannot be a “participating partner institution” with another CTSA hub for the purpose of calculating the “maximum total amount that can be requested.” Back to top Training and Career Development Are the recommended number of scholars referenced in PAR 15-304 indicated for the entire grant period? The FOA states: "The recommended number of scholars to budget for in the application is four for small hubs (total anticipated CTSA Program award <$4.5M DC), six for medium hubs (total anticipated CTSA Program award $4.5M-$6M DC), and nine for large hubs (total anticipated CTSA Program award >$6M-$7.5M DC)." No. The recommended number of scholars to budget for in the application applies to each grant year, not the entire grant project period. For small hubs, applicants may budget for a total of four scholar appointments for each grant year including both new and re-appointments. Can long-term trainee appointments between pre- and post-doctoral applicants change each year, depending on the pool of applicants keeping the same number of approved slots? The selection of pre- and post-doctoral appointments must be specified in the application for the entire grant project period (five years). The division of slots may be altered over the course of the grant period in a cost-neutral manner with NCATS prior approval. Is there a limit on the number of mentors that may be submitted under the Institutional Career Development Core and the Training Core (as applicable)? No, there is no limit on the number of mentors who may be listed for the Institutional Career Development Core or the Training Core. Participating faculty members should be listed in Table 2 of the required training data tables. When budgeting for the KL2 program, can the institution supplement the NIH salary up to a level that is consistent with the institution’s salary scale? Yes, the institution may supplement the NIH salary level so that it is consistent with the institution’s salary scale. Is budgeting salary support for the Project Lead and staff to support the program allowed as part of the KL2 budget? Yes, all budget components of the Institutional Career Development Award are included in the KL2 budget, including the Project Lead and staff members. Is budgeting salary support for the Project Lead to support the program allowed as part of the TL1 budget? No, the Project Lead and staff salaries (including travel) for the optional Training Core should be included in the UL1 Administrative Core budget. Costs should be reasonable for the size of the training program and well justified. Because these funds will be excluded from the total costs maximum award that can be requested for the U + K components and excluded from the recommended 10 percent limitation for the Administrative Core, applicants must clearly identify the costs associated with the Training Core in their budget justification. Training Core costs directly related to training appointees (stipends, tuition, trainee travel and training-related expenses) should be requested in the Training Core budget. The budget section of the Training Core (TL) component indicates that in addition to stipends for trainees, training-related expenses also can be requested. May “training-related expenses” include salary and travel support for Training Core Leader(s) and other staff needed to administer the program? No, the salaries and fringe benefits for the other personnel should not be included in the Training Core component budget, but rather in the UL1 budget section. The NRSA Training Core stipends, tuition, trainee travel and training-related expenses should be requested under the Training Core budget section. Does the $120,000 per scholar salary support cap include benefits? No, according to the PAR 15-304 instructions for calculating the salary for scholars (Institutional Career Development Core), you may include support for $120,000 plus fringe benefits. The PAR also states that the average total costs per scholar must not exceed $180,000 in direct costs per year. What training data tables are required for the T and K components? K Component Data Table: The updated Forms E SF424 instructions provide a detailed description of the research training tables. The Introduction to the Data Tables linked under the updated Forms E SF424 instructions provides an overview of the tables, their contents, and the templates. Tables 2 and 8C are required for new, renewal, and revision applications. T Component Data Tables: The required data tables will differ depending on the type of application (i.e., new versus renewal/revision) and whether the program includes predoctoral training, postdoctoral training, short-term training, or mixed variations of these categories. The updated Forms E SF424 instructions provide a detailed description of the required data tables. The descriptive guidance for Scholar Candidates* no longer requests information on the candidate pool, recruitment, nomination and selection. Is this information no longer required? The Scholar Candidate* information still is required, and applicants should follow the SF424 (R&R) Application Guide instructions referenced under the Training Program Plan —Form E series: *Substitute the term “scholars” for all references to “trainees” in the SF424 (R&R) Application Guide. Trainee Candidates Describe, in general terms, the size and qualifications of the pool of trainee candidates, including information about the types of prior clinical and research training and the career level required for the program. Describe specific plans to recruit candidates and explain how these plans will be implemented (see also "Section C. Recruitment Plan to Enhance Diversity" within the Program Plan). Describe the nomination and selection process to be used to select candidates who will be offered admission to the program and criteria for trainees’ reappointment to the program. Additional guidance concerning the Recruitment Plan to Enhance Diversity is also provided in the SF424 and should address the comprehensive recruitment effort, including those who are underrepresented in biomedical research. Finally, it is incumbent for applicants to address the Scored Review Criteria as referenced in Section V. Application Review Information for both the K and T components. Back to top For More Information What if I have additional questions? Send your questions via email to CTSAFOAQuestions@mail.nih.gov. Answers in response to emailed questions may be added to this page at a later date.	CTSA PAR Frequently Asked Questions	CTSA PAR Frequently Asked Questions
3343	Work with ETB	The ETB working model is highly collaborative. We always encourage new partnership opportunities, including target-focused disease projects with NIH and external research laboratories as well as disease foundations and biotechnology companies. If you have a potential disease target you’d like to screen, submit a request to work with ETB! Contact the ETB Team with the following details: A summary of the idea/vision Research goals Project needs Your level or area of biology expertise NCATS welcomes all ETB project proposals. After project selection, staff actively communicate with all collaborators to discuss the target of interest and the best path forward.
3340	ETB Resources	The ETB offers numerous state-of-the-art resources to provide scientists with access to the entire spectrum of drug discovery research, helping the Center serve NCATS’ broader mission of translating foundational discoveries in the laboratory to the clinic. ETB resources include: Core technologies Automation Compound management Analytical chemistry Informatics Diverse collections of small molecule libraries More than 450,000 compounds Potent clinical candidates with annotated mechanisms NCATS Pharmaceutical Collection Advanced instrumentation enabling completion of high-throughput, high-content and advanced assays using multiple detection technologies
3341	ETB Expertise	The ETB is composed of three drug discovery teams, each with dedicated biologists, chemists and informatics scientists. These teams are uniquely designed to handle small molecule discovery efforts, including early assay optimization, state-of-the-art high-throughput screening, early hit selection, advanced medicinal chemistry driven by structure-activity relationships, virtual screening, and molecular modeling and docking. Each team showcases specialized areas of expertise covering a wide spectrum of biological targets and human pathologies, including: 3-D cell culture and tissue/organoid models Advanced cell-based models of disease Autophagy Cancer Cellular thermal shift assays Deubiquitinating enzymes DNA damage and replication Epigenetics Enzymatic assays High-throughput cell-based models and high-content screening Immunological and differentiation assays Induced pluripotent stem cell–based assays (retinal pigment epithelium, neurological disorders) Infectious diseases Kinases Metabolic targets (cancer and inborn errors of metabolism) Yeast/bacterial assays
3332	NCATS Matches Researchers with Pharmaceutical Industry Assets to Test Ideas for New Therapies	For every drug that is approved by the U.S. Food and Drug Administration, many others are not due to lack of effectiveness in treating the disease they were designed to target. NCATS leads initiatives to repurpose some of these partially developed investigational drugs (also known as assets) to treat new disease indications and get more treatments to more patients more quickly. Through its Discovering New Therapeutic Uses for Existing Molecules (New Therapeutic Uses) program, NCATS recently awarded nearly $3 million to support four academic research groups that will test a selection of pharmaceutical industry assets for new therapeutic uses. The awarded projects are aimed at finding therapies for: Type 2 diabetes Glioblastoma (one of the most aggressive brain tumors in adults) Acute myeloid leukemia (an aggressive blood cancer) Chagas disease (a neglected tropical disease that causes heart, digestive and neurological problems) Each award recipient will test a selected asset for its effectiveness against a previously unexplored disease or condition. The industry partners for these projects are AstraZeneca and Sanofi. “The New Therapeutic Uses program helps re-engineer the research pipeline by crowdsourcing pharmaceutical company assets that already have cleared several key steps in the development process, including initial safety testing in humans,” said Christine M. Colvis, Ph.D., NCATS director of drug development partnership programs. “This approach enables scientists nationwide to contribute their expertise to accelerate the pace at which discoveries are turned into treatments and cures for patients.” “Too often academic, industrial and community partners operate in separate silos,” said Craig Wegner, Ph.D., head of the Boston Emerging Innovations Unit, Scientific Partnering & Alliances within AstraZeneca's Innovative Medicines and Early Development Biotech Unit. “The crowdsourcing aspect of the New Therapeutic Uses initiative enables these parties — who might otherwise not have connected ― to combine their knowledge and resources to push the boundaries of medical science.” The 2015 projects are: Anti-inflammatory Small Drug as Adjunctive Therapy to Improve Glucometabolic Variables in Obese, Insulin-Resistant Type 2 Diabetic Patients Academic Partner: Nick Giannoukakis, Ph.D., Allegheny Health Network Research Institute, Pittsburgh Industry Partner: AstraZeneca Evaluation of AZD9291 in Glioblastoma Patients with Activated EGFR Academic Partners: Madan M. Kwatra, Ph.D., and Glenn J. Lesser, M.D., Duke University, Durham, North Carolina Industry Partner: AstraZeneca Evaluation of a Cathepsin S Inhibitor as a Potential Drug for Chagas Disease Academic Partners: James H. McKerrow, M.D., Ph.D., University of California, San Diego Industry Partner: Sanofi Wee1 and HDAC Inhibition in Relapsed/Refractory AML Academic Partner: Steven Grant, M.D., Massey Cancer Center, Virginia Commonwealth University, Richmond Industry Partner: AstraZeneca “There is a longstanding need to develop new treatments for Chagas disease, the most common parasitic disease in the Americas,” said Elias Zerhouni, M.D., president of Sanofi Global R&D. “Through collaborations facilitated by the New Therapeutic Uses initiative, we have an opportunity to address this neglected public health issue and deliver real value to patients with unmet medical needs in developing regions across North and South America.” YouTube embed video: &lt;a data-cke-saved-href=&quot;https://www.youtube-nocookie.com/embed/sMlA2qeR9MQ&quot; href=&quot;https://www.youtube-nocookie.com/embed/sMlA2qeR9MQ&quot;&gt;https://www.youtube-nocookie.com/embed/sMlA2qeR9MQ&lt;/a&gt; Nick Giannoukakis, Ph.D., explains his research project on type 2 diabetes. (Allegheny Health Network Research Institute Video) The 2015 awards will fund projects for researchers to conduct preclinical validation and additional safety and tolerability studies as needed. If specific milestones are met, investigators can begin clinical feasibility studies or proof-of-concept clinical trials to explore whether the selected assets may be effective as treatments for other diseases. The projects will be supported for up to three years. The pilot phase of the New Therapeutic Uses program tested the utility of template agreements established with each industry partner that proved successful in facilitating negotiations. The agreements reduced the time required to establish collaborations between industry and academia to about three months from the more typical nine months to one year. NCATS announced another early program success in March 2015: New Therapeutic Uses support to a Yale research team led to an expedited clinical trial to test an experimental cancer drug as an Alzheimer’s treatment. NCATS leads the New Therapeutic Uses program with additional scientific expertise provided by the National Cancer Institute; National Heart, Lung, and Blood Institute; National Institute of Allergy and Infectious Diseases; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Mental Health; National Institute of Neurological Disorders and Stroke; National Institute on Aging; National Institute on Alcohol Abuse and Alcoholism; and National Institute on Drug Abuse. For more information, visit NCATS’ New Therapeutic Uses Web page. Posted July 2015
3330	2015 NIH–Industry Partnerships Projects	In July 2015, NCATS announced nearly $3 million to fund cooperative agreements with four academic research groups to conduct preclinical validation studies, clinical feasibility studies or proof-of-concept clinical trials to test whether the selected assets may be effective against a previously unexplored disease target. Four disease areas are represented: Type 2 diabetes Acute myeloid leukemia (an aggressive blood cancer) Glioblastoma (one of the most aggressive brain tumors in adults) Chagas disease (a neglected tropical disease causing heart, digestive and neurological problems) Industry partner companies are providing the drug and matched placebo as well as data and other resources at no cost to NCATS or the academic institutions. These projects are in response to PAR-14-210, PAR-14-211 and PAR-14-212: Anti-inflammatory Small Drug as Adjunctive Therapy to Improve Glucometabolic Variables in Obese, Insulin-Resistant Type 2 Diabetic Patients Evaluation of AZD9291 in Glioblastoma Patients with Activated EGFR Evaluation of a Cathepsin S Inhibitor as a Potential Drug for Chagas Disease Wee1 and HDAC Inhibition in Relapsed/Refractory AML Anti-inflammatory Small Drug as Adjunctive Therapy to Improve Glucometabolic Variables in Obese, Insulin-Resistant Type 2 Diabetic Patients Allegheny Health Network Research Institute Principal Investigator: Nick Giannoukakis, Ph.D. Grant Number: 1-UH3-TR001372-01 More than 29 million Americans have type 2 diabetes (T2D), a debilitating disorder and the seventh leading cause of death. The main risk factor for T2D is obesity, which leads to chronic inflammation that can disrupt the body’s sensitivity to insulin, a hormone associated with T2D that controls blood sugar levels. T2D inflammation also is linked to higher risk for cardiovascular disease. The body’s white blood cells, which are involved in the body’s immune response, may underlie T2D inflammation. This research team will test a leukocyte-selective anti-inflammatory compound as an add-on medication for obese, insulin-resistant T2D patients. The investigators will measure its ability to improve T2D and reduce inflammation. This work may lead to an improved T2D therapy that could enable better outcomes and reduces risk for other diseases. The compound also may be useful for treating other inflammation-associated disorders. Watch Giannoukakis discuss this research: YouTube embed video: &amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;a data-cke-saved-href=&amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;https://www.youtube.com/watch?v=sMlA2qeR9MQ&amp;amp;amp;amp;amp;amp…; href=&amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;https://www.youtube.com/watch?v=sMlA2qeR9MQ&amp;amp;amp;amp;amp;amp…; Evaluation of AZD9291 in Glioblastoma Patients with Activated EGFR Duke University Principal Investigators: Madan M. Kwatra, Ph.D., and Glenn J. Lesser, M.D. Grant Number: 1-UH2-TR001370-01 Glioblastoma (GBM) is one of the most aggressive and common brain tumors in adults. Current treatments have failed to extend median survival time beyond 15 months, indicating an urgent need for a more effective GBM therapy. To achieve this goal, scientists must better understand the molecular machinery that drives GBM. Recent work indicates that a subset of GBM tumors show elevated activity of a protein known to affect tumor growth called epidermal growth factor receptor (EGFR). Tumors with overactive EGFR also have enhanced activity of another protein called HER2. AZD9291 — a compound that can cross the blood-brain barrier and was originally designed to treat lung cancer — blocks the activity of both EGFR and HER2. The proposed studies are designed to find an effective therapy for glioblastoma patients with an activated form of EGFR. This work could lead to the development of a new, more effective and more precise treatment strategy for a specific group of GBM patients. This image shows a series of four magnetic resonance imaging (MRI) scans of the brain. On the far left is a normal brain. In the middle on left and right are glioblastoma tumors in the brain’s frontal and occipital lobes, respectively; the scans show significant swelling of the surrounding tissue. On the far right is a glioblastoma tumor in the occipital lobe of a child’s brain. (Wake Forest School of Medicine Photo) Evaluation of a Cathepsin S Inhibitor as a Potential Drug for Chagas Disease University of California, San Diego Principal Investigator: James H. McKerrow, M.D., Ph.D. Grant Number: 1-UH2-TR001369-01 Chagas disease is a neglected tropical disease that currently affects an estimated 7 million people, according to the World Health Organization. Chagas disease is responsible for more than 10,000 deaths worldwide each year, making it the leading cause of heart failure in Latin America and an emerging infection in the U.S. The disease is caused when an insect transmits the Trypanosoma cruzi (T. cruzi) parasite to a person through blood, causing heart, digestive and neurological problems. There are no therapies for Chagas disease approved by the Food and Drug Administration (FDA). The current treatments cause negative side effects and are largely ineffective at later stages of the disease, demonstrating a need for an improved therapy that targets T. cruzi. Scientists have shown that a compound that blocks a critical parasitic enzyme can cure Chagas disease and prevent heart problems in infected animals. Unfortunately, this compound has additional unwanted effects. A drug that works using a similar mechanism but lacks these unwanted effects — called SAR114137 — was originally designed to treat chronic pain and may be a good therapeutic candidate for Chagas disease. These investigators will confirm the drug’s antiparasitic activity in cell culture studies and in infected animals, then test its safety and effectiveness in humans with the disease. This work could lead to a more effective treatment for a neglected and deadly tropical disease. Wee1 and HDAC Inhibition in Relapsed/Refractory AML Virginia Commonwealth University Principal Investigator: Steven Grant, M.D. Grant Number: 1-UH2-TR001373-01 Despite advances in understanding the molecular basis of acute myelogenous leukemia (AML), an aggressive blood cancer, patient outcomes often are grim, particularly for individuals with certain mutations or with recurrent or treatment-resistant disease. Although no current therapy exists, scientists have found that a protein called Wee1 represents a potential therapeutic target in AML. AZD1775 is an oral drug that inhibits Wee1, but until now, clinicians have used it primarily for treating other forms of cancer, particularly solid tumors, and generally in combination with standard chemotherapy. Another drug class, histone deacetylase inhibitors (HDACis), recently received orphan drug status from the FDA for the treatment of AML. The investigators found that AZD1775 and HDACis work together to kill human leukemia cells and that the drug combination also improves survival in mice with AML. For this project, the team will continue to investigate the molecular basis of the drugs’ actions in mice and test its safety and effectiveness in patients with recurrent or treatment-resistant AML. These efforts may lead to a new and potentially more effective treatment strategy for patients with this deadly cancer. Steven Grant, M.D., from the Massey Cancer Center at Virginia Commonwealth University (VCU), investigates novel combination of drugs that cooperate to kill leukemia cells. (VCU Massey Cancer Center Photo)	2015 NIH–Industry Partnerships Projects	2015 NIH–Industry Partnerships Projects
3331	2013 NIH–Industry Partnerships Projects	In June 2013, NIH announced funding for nine cooperative agreements designed to match academic research groups with selected compounds from industry as part of the New Therapeutic Uses program. The goal is to use molecules that already have undergone significant research and development by the pharmaceutical industry to more quickly advance new treatments for patients. The funded research projects listed below address eight disease areas and are in response to RFA-TR-12-004 and RFA-TR-12-005. The Efficacy and Safety of a Selective Estrogen Receptor Beta Agonist (LY500307) Fyn Inhibition by AZD0530 for Alzheimer's Disease Medication Development of a Novel Therapeutic for Smoking Cessation A Novel Compound for Alcoholism Treatment: A Translational Strategy Partnering to Treat an Orphan Disease: Duchenne Muscular Dystrophy Reuse of ZD4054 for Patients with Symptomatic Peripheral Artery Disease Therapeutic Strategy for Lymphangioleiomyomatosis Therapeutic Strategy to Slow Progression of Calcific Aortic Valve Stenosis Translational Neuroscience Optimization of GlyT1 Inhibitor The Efficacy and Safety of a Selective Estrogen Receptor Beta Agonist (LY500307) Indiana University Principal Investigator: Alan Breier, M.D. Grant Number: 1-UH2TR000955-01 Schizophrenia is a mental illness that affects about 1 percent of the population. It reduces the ability to express emotion, impairs social behavior, and reduces working and verbal memory (cognitive impairment), among other symptoms. The effects can devastate relationships and reduce a person's ability to obtain an education or hold a job, and the burden on caretakers for people with schizophrenia is high. Unfortunately, people with schizophrenia do not respond well to any medications approved by the Food and Drug Administration. The hormone estrogen appears to offer some relief from these symptoms; however, it can feminize males and cause uterine cancer and heart disease in premenopausal women. This research team will test a drug candidate that mimics estrogen's action in the body but lacks its negative side effects to see if the drug candidate is safe and if it relieves symptoms in patients with schizophrenia. If the drug candidate proves effective, it could improve patients' functional ability and quality of life. Listen to Breier discuss this research: This content requires the free Adobe Flash Player. Get Flash. You can listen to the audio with JavaScript turned on. To view it without JavaScript and Flash, you can access the text-only version of the audio. jwplayer('mediaspace').setup({ 'flashplayer': '/sites/all/themes/ncats-2014/js/jwplayer-5-master/player.swf', 'controlbar': 'bottom', 'file': '/files/NTU-Breier.mp3', 'width': 'auto', 'height': '24' }); Right-click to download a transcript (1 KB) Learn more about this project in the NIH RePORTER. Fyn Inhibition by AZD0530 for Alzheimer's Disease Yale University Principal Investigators: Stephen M. Strittmatter, M.D., Ph.D., Haakon Berge Nygaard, M.D., Ph.D., and Christopher H. Van Dyck, M.D. Grant Number: 1-UH2TR000967-01 Alzheimer's disease is a neurological disorder that worsens over time with no effective treatment to slow or halt its progression. One in eight older Americans (about 5.2 million) has Alzheimer's, at a cost of $200 billion in 2012. As the U.S. population ages, estimates predict as many as 14 million Americans may have Alzheimer's disease by 2050. Fyn kinase, a type of protein in the Src kinase family, is involved in triggering Alzheimer's disease. In a mouse model, it impaired memory and reduced signals between brain cells, but removing it stopped these symptoms. This research team will test an investigational drug that blocks Fyn kinase activity, first in a mouse model, then in Alzheimer's patients for safety. The next step will be to study the drug's effectiveness in slowing disease progression in a larger population with mild Alzheimer's disease. The goal is to provide evidence for a large, multisite study of the investigational drug as a therapy to slow or halt progression of Alzheimer's disease. Watch Strittmatter discuss this research: YouTube embed video: https://www.youtube.com/watch?v=fngrY-hDRCA Learn more about this project in the NIH RePORTER. Medication Development of a Novel Therapeutic for Smoking Cessation Virginia Commonwealth University and University of Pittsburgh Principal Investigators: Darlene H. Brunzell, Ph.D. (VCU), and Kenneth Alan Perkins, Ph.D. (Pitt) Grant Number: 1-UH2TR000958-01 Cigarette smoking is the leading preventable cause of death in the United States, causing nearly 1 in 5 deaths each year. Smoking causes coronary heart disease and a variety of cancers, and it increases the risk for stroke and many other conditions. The health care costs and lost productivity among cigarette smokers exceeds $200 billion annually. Despite these staggering costs, nearly 50 million Americans smoke. Most say they want to quit, but few are successful with currently approved therapies, suggesting the need for better treatment options. This research team will use studies in rodents and clinical trials in smokers to test an existing compound as a treatment for tobacco cessation. The results of this research could lead to a new drug to treat nicotine dependence and might provide an effective cessation treatment for the most vulnerable smokers. Listen to Brunzell discuss this research: This content requires the free Adobe Flash Player. Get Flash. You can listen to the audio with JavaScript turned on. To view it without JavaScript and Flash, you can access the html text-only version of the audio. jwplayer('mediaspace3').setup({ 'flashplayer': '/sites/all/themes/ncats-2014/js/jwplayer-5-master/player.swf', 'controlbar': 'bottom', 'file': '/files/NTU-Brunzell.mp3', 'width': 'auto', 'height': '24' }); Learn more about this project in the NIH RePORTER. A Novel Compound for Alcoholism Treatment: A Translational Strategy University of Rhode Island and National Institute on Alcohol Abuse and Alcoholism and National Institute on Drug Abuse Principal Investigators: Fatemeh Akhlaghi, Pharm.D., Ph.D. (URI), and Lorenzo Leggio, M.D., Ph.D., M.Sc. (NIAAA/NIDA) Grant Number: 1-UH2TR000963-01 Excessive alcohol use is responsible for approximately 80,000 deaths each year in the U.S. and costs the nation about $224 billion in health care costs and lost productivity; indeed, alcohol dependence affects approximately 10 percent of the U.S. population. However, only a few drugs approved by the Food and Drug Administration are available to treat alcohol dependence, and their effects are not optimal. This research team will test an oral medication that blocks a hormone called ghrelin to see if the drug is safe and if it reduces alcohol dependence. Ghrelin stimulates appetite and also can trigger alcohol craving and consumption. Both animal and human experiments suggest that blocking ghrelin activity could be a novel and promising way to treat alcohol dependence. The research team also will seek to better understand how the ghrelin-blocking drug interacts with alcohol in humans. The investigational drug could reduce the prevalence of disease and deaths associated with excess alcohol use and may be used in further studies to treat other addictions, such as tobacco dependence. Listen to Leggio discuss this research: This content requires the free Adobe Flash Player. Get Flash. You can listen to the audio with JavaScript turned on. To view it without JavaScript and Flash, you can access the html text-only version of the audio. jwplayer('mediaspace4').setup({ 'flashplayer': '/sites/all/themes/ncats-2014/js/jwplayer-5-master/player.swf', 'controlbar': 'bottom', 'file': '/files/NTU-Leggio.mp3', 'width': 'auto', 'height': '24' }); Learn more about this project in the NIH RePORTER. Partnering to Treat an Orphan Disease: Duchenne Muscular Dystrophy Kennedy Krieger Institute and University of Washington Principal Investigators: Kathryn R. Wagner, M.D., Ph.D. (KKI), and Stanley C. Froehner, Ph.D. (UW) Grant Number: 1-UH2TR000966-01 Duchenne muscular dystrophy (DMD) is a severe, disabling and fatal disorder. DMD affects approximately 1 in 5,000 male births worldwide. Children are born with normal strength, lose the ability to walk in early adolescence and die in early adulthood. The only accepted treatment is corticosteroids, which offer only mild benefits and have many side effects. This research team will test an oral, investigational drug by Sanofi to see if it is effective in a mouse muscular dystrophy model and safe in young animals. This will be followed by testing for safety and ideal dose level in DMD patients. In the next phase of the study, a multisite clinical trial will test the investigational drug to provide evidence of its potential benefit to DMD patients. Because DMD is a fatal disease, this study could be a pivotal turning point in obtaining Food and Drug Administration approval for a novel DMD therapeutic. Watch Wagner discuss this research: YouTube embed video: https://www.youtube.com/watch?v=C4XOI23v0SA Learn more about this project in the NIH RePORTER. Reuse of ZD4054 for Patients with Symptomatic Peripheral Artery Disease University of Virginia Principal Investigator: Brian H. Annex, M.D. Grant Number: 1-UH3TR000959-01 Peripheral artery disease (PAD) is a major complication of cholesterol build-up that hardens artery walls and blocks blood flow, a condition called atherosclerosis. In PAD, this cholesterol buildup in the leg arteries, causes leg pain during walking and places major limits on a patient's quality of life. PAD affects more than 8 million Americans, but the numbers rise with older age, diabetes and smoking, as do the associated health care costs. Cholesterol-reducing drugs, medications to relieve high blood pressure and medications like aspirin to prevent clotting are recommended for patients with PAD; however, they do not improve blood flow to the legs. This research team will test an investigational drug for its ability to improve blood flow in PAD patients' legs. The investigational drug might relieve leg pain, help patients walk further and longer, and reduce the costs of hospitalization and treatment. Listen to Annex discuss this research: This content requires the free Adobe Flash Player. Get Flash. You can listen to the audio with JavaScript turned on. To view it without JavaScript and Flash, you can access the html text-only version of the audio. jwplayer('mediaspace6').setup({ 'flashplayer': '/sites/all/themes/ncats-2014/js/jwplayer-5-master/player.swf', 'controlbar': 'bottom', 'file': '/files/NTU-Annex.mp3', 'width': 'auto', 'height': '24' }); Learn more about this project in the NIH RePORTER. Therapeutic Strategy for Lymphangioleiomyomatosis Baylor College of Medicine Principal Investigator: N. Tony Eissa, M.D. Grant Number: 1-UH2TR000961-01 Lymphangioleiomyomatosis (LAM) is a progressive lung disease in which atypical cells, originating somewhere in the body, spread throughout the lungs, gradually blocking small airways and producing cysts. Typically, the disease progresses slowly, but eventually it can restrict breathing enough to cause death. LAM almost exclusively affects women of childbearing age. At this time, no proven cure exists for LAM. This research team has discovered that a type of protein called Src kinase is active in LAM cells and is important for cell growth and cells' ability to move around and invade tissues. This study aims to determine if blocking Src activity using an investigational drug is safe and can reduce the growth and the spread of LAM cells. Listen to Eissa discuss this research: This content requires the free Adobe Flash Player. Get Flash. You can listen to the audio with JavaScript turned on. To view it without JavaScript and Flash, you can access the html text-only version of the audio. jwplayer('mediaspace7').setup({ 'flashplayer': '/sites/all/themes/ncats-2014/js/jwplayer-5-master/player.swf', 'controlbar': 'bottom', 'file': '/files/NTU-Eissa.mp3', 'width': 'auto', 'height': '24' }); Learn more about this project in the NIH RePORTER. Therapeutic Strategy to Slow Progression of Calcific Aortic Valve Stenosis Mayo Clinic Principal Investigators: Jordan D. Miller, Ph.D., Maurice Enriquez-Sarano, M.D., and Hartzell V. Schaff, M.D. Grant Number: 1-UH2TR000954-01 Calcific aortic valve stenosis is a condition in which the heart valve to the aorta narrows and cannot open fully. This disease affects 3 percent of Americans older than age 65, and more than 5 million people are diagnosed with heart valve disease of some kind each year. Even for patients with only moderate aortic valve stenosis, fewer than 40 percent survive for five years after being diagnosed. No effective treatments exist to slow progression of aortic valve calcification; replacing the heart valve is the only treatment for advanced stenosis. This research team will test the safety of a Sanofi investigational drug in heart valve disease patients. The research team will test the investigational drug to provide proof of concept in slowing progression of stenosis in humans, with the potential to reduce death and illness caused by progression of calcific aortic valve disease. Listen to Miller discuss this research: This content requires the free Adobe Flash Player. Get Flash. You can listen to the audio with JavaScript turned on. To view it without JavaScript and Flash, you can access the html text-only version of the audio. jwplayer('mediaspace8').setup({ 'flashplayer': '/sites/all/themes/ncats-2014/js/jwplayer-5-master/player.swf', 'controlbar': 'bottom', 'file': '/files/NTU-Miller.mp3', 'width': 'auto', 'height': '24' }); Right-click to download a transcript (1KB) Learn more about this project in the NIH RePORTER. Translational Neuroscience Optimization of GlyT1 Inhibitor Yale University Principal Investigator: John H. Krystal, M.D. Grant Number: 1-UH2TR000960-01 Problems with attention, memory and planning (cognitive deficits) are core symptoms of schizophrenia, with no approved treatments. The disease affects about 1 percent of the population, and these cognitive deficits can reduce a person's ability to obtain an education or hold a job. Schizophrenia also places a heavy burden on families and caretakers. Researchers know that abnormal function of a receptor called NMDAR, which is needed to transmit signals between brain cells, contributes to the cognitive deficits in schizophrenia. An experimental drug may reduce this abnormal function in NMDAR. Using brain imaging studies, this research team will determine the safest dose of the experimental drug in healthy subjects. A novel clinical trial will follow to assess whether the experimental drug is effective by combining it with mind exercises to treat cognitive deficits in schizophrenia patients. Restoring NMDAR function in patients' brains might be an effective treatment for the cognitive deficits in schizophrenia. Listen to Krystal discuss this research: This content requires the free Adobe Flash Player. Get Flash. You can listen to the audio with JavaScript turned on. To view it without JavaScript and Flash, you can access the html text-only version of the audio. jwplayer('mediaspace9').setup({ 'flashplayer': '/sites/all/themes/ncats-2014/js/jwplayer-5-master/player.swf', 'controlbar': 'bottom', 'file': '/files/NTU-Krystal.mp3', 'width': 'auto', 'height': '24' }); Right-click to download a transcript (1KB) Learn more about this project in the NIH RePORTER.
3342	ETB Teams	Adenine Team Guanine Team Thymine Team Adenine Team Scientific Areas of Focus Cancer Deubiquitinating enzymes Epigenetics DNA damage and replication Infectious diseases Team Members Biology Team Lead: Anton Simeonov, Ph.D. Chemistry Team Lead: Juan Marugan, Ph.D. Research Scientists: Bolormaa Baljinnyam, Ph.D., biology Ganesha Bantukallu, chemistry George Dorjsuren, biology Xin Hu, Ph.D., informatics Sankalp Jain, Ph.D., informatics Dan Jansen, chemistry Steve Kales, Ph.D., biology Diane Luci, M.S., chemistry Natalia Martinez, Ph.D., biology Katie Pohida, chemistry (Intramural Research Training Award fellow) Hongmao Sun, Ph.D., informatics Shyh-Ming Yang, Ph.D., chemistry Adam Yasgar, biology Guanine Team Scientific Areas of Focus Cancer Enzymatic assays Kinases Metabolic targets (cancer and inborn errors of metabolism) Cellular thermal shift assays High-throughput cell-based models and high-content screening Team Members Biology Team Lead: Matt Hall, Ph.D. Chemistry Team Lead: Juan Marugan, Ph.D. Informatics Team Lead: Min Shen, Ph.D. Research Scientists: Ken Cheng, Ph.D., biology Nathan Coussens, Ph.D., biology Surendra Karavadhi, chemistry Colin Kelly, biology Li Liu, M.S., chemistry Dan Urban, biology Ya-Qin Zhang, biology Wei Zhao, biology Hu Zhu, Ph.D., biology Thymine Team Scientific Areas of Focus Cancer Induced pluripotent stem cell–based assays (retinal pigment epithelium, neurological disorders) Advanced cell-based models of disease 3-D cell culture and tissue/organoid models Immunological and differentiation assays Autophagy Yeast/bacterial assays Team Members Biology Team Lead: Mark J. Henderson, Ph.D. Chemistry Team Lead: Juan Marugan, Ph.D. Informatics Team Lead: Noel Southall, Ph.D. Research Scientists: Elena Barnaeva, biology Raul Calvo, M.S., chemistry Chris Dextras, biology Andrés Dulcey, Ph.D., chemistry Rajarshi Guha, Ph.D., informatics Xin Hu, Ph.D., informatics Madhu Lal-Nag, Ph.D., biology Samarjit Patnaik, Ph.D., chemistry Tej Poudel, Ph.D., medicinal chemistry Wenjuan Ye, M.B., biology Xiaohu Zhang, biology

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