NCATS HEAL Collaboration Opportunities

Capabilities across NCATS’ intramural program can be applied to HEAL-related projects that address questions relevant to pain, addiction and overdose. Depending on the nature of the proposal, collaboration capabilities in more than one NCATS area of expertise may be applied. Specifically, collaboration opportunities are available with or among the following:

  • Stem Cell Translation Laboratory (SCTL) — Pain, addiction and overdose experts can work with NCATS’ SCTL staff to improve prediction of in vivo human effects of lead compounds by testing them using iPSC platform capabilities. Collaborators can also advance understanding of different types of pain, the differences in individual responses to pain, and the risk for developing chronic pain or addiction. Capabilities include screening, scalable production of the most relevant human cell types and real-time functional characterization. Specifically:
    • Scalable and fully automated protocols using robotic systems to generate pure cultures of sensory neurons (nociceptors) and other neuronal subtypes (e.g., GABAergic, glutamatergic, dopaminergic) in large quantities under chemically defined conditions
    • Imaging technologies (e.g., high-content confocal microscopy, calcium imaging, optogenetics)
    • High-throughput electrophysiology methods (high-density multi-electrode arrays [26,400 electrodes/well]) to streamline monitoring of electrical activity at very high spatio-temporal resolution
    • Measurement of cell signaling pathways, metabolism and specific targets (e.g., cyclic AMP, PKA activity, CREB phosphorylation, energy metabolism)
    • Longitudinal tracking of cell behavior with multiple measurements over days, weeks or months
    • Combined single-cell transcriptomic and proteomic analyses that provide information on drug response in individual nociceptors and other neuronal phenotypes
  • 3-D Tissue Bioprinting — Pain, addiction and overdose experts can collaborate with NCATS experts to biofabricate 3-D functional tissues using autologous human cells derived from iPSC cells. Such biofabrication holds the promise of personalized tissue production for drug testing by providing the 3-D multicellular architecture found in human systems. NCATS integrates advances in tissue engineering technologies, 3-D bioprinters, biocompatible polymers and hydrogels, and quantitative methods to validate the morphology and function of human tissues. Capabilities include functionally and physiologically disease-relevant assay platforms, in microwell plate format, to increase the throughput of drug testing and create models that are better predictors of human response to new drugs. Specifically:
    • Biofabrication of 3-D tissues in a microwell plate format
    • Scale up and automated production of iPSC-derived somatic cells
    • Protocols for fast, high-throughput quantitative 3-D measurements using imaging, mass spectrometry and genomics
    • Screening of drugs in 3-D tissue-in-a-dish relevant models
    • Testing compounds in 3-D blood-brain-barrier models
    • Joint development of engineering and 3-D tissue technology platforms
    • Federated, cloud-based process for data acquisition and storage with access for knowledge mining through artificial intelligence methods
  • Pharmacological Probe Development — NCATS scientists can help investigators who have identified pain, addiction and overdose targets for analysis through its quantitative high-throughput screening (qHTS) expertise. Using qHTS, Center staff can identify promising compounds to modulate novel targets. NCATS’ medicinal chemists can provide optimization to impute the improved potency, selectivity and pharmacokinetic properties required of an in vitro/in vivo pharmacological probe of the novel target. These probes can then be tested using the iPSC or 3-D bioprinting platforms described above or in animal efficacy models. Capabilities include:
    • Adapting assays for qHTS and developing new assays (e.g., myenteric neurons and cultured locus coeruleus [LC] neurons)
    • Counterscreen/confirmatory assays
    • Cheminformatics tools
    • Medicinal chemistry to optimize compounds
    • Dose/response
  • Enabling Investigational New Drug (IND) Applications — Investigators/companies who have identified promising small molecules, biologics or gene therapies to treat pain, addiction or overdose can form joint project teams with NCATS’ Therapeutic Development Branch (TDB) staff — including Bridging Interventional Development Gaps and Therapeutics for Rare and Neglected Diseases scientists — to develop IND-ready therapies for consideration by the Food and Drug Administration for clinical testing. Capabilities available through the TDB include:
    • Medicinal chemistry to finalize declaration of clinical candidates
    • Pharmacokinetics and pharmacodynamics
    • Toxicological profiling
    • Formulation for optimal bioavailability
    • Good manufacturing practice to scale up the production of the compound for clinical testing
    • Project management
    • Expertise with a range of therapeutic modalities, including small molecule, biologic and gene therapies
    • Repurposing of approved therapies