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Novel Tools for Investigating Brain-derived GPCRs in Mental Health Research (R43/R44 Clinical Trial Not Allowed)


  1. Background

    G-protein coupled receptor proteins (GPCRs) are membrane bound proteins that serve to modulate cellular activities. Many of the GPCRs have potential significance in healthy mental function and in mental disorders, including receptors for most neurotransmitters and neuropeptides. Drugs targeting GPCRs are currently used in the treatment of mental disorders such as schizophrenia, anxiety and depression, yet the similarity of receptor subtypes has precluded the development of subtype selective agonists and antagonists as improved therapeutics with fewer side effects. Recent advances in GPCR biology have led to interest in biased agonism, allosteric modulators, GPCR dimers/multimers, and 3-D structures as potential avenues to the development of compounds selective for particular receptor subtypes and downstream signaling pathways. Such compounds may hold promise both as research tools and lead compounds for drug development.

    Research Objectives

    The purpose of this funding opportunity is to encourage small businesses to develop technologies and approaches (i.e., novel ways to use new or existing technologies) that will enable researchers to better understand and manipulate the dynamic structure and/or function of brain localized GPCRs and/or potentially identify novel selective and specific agonists, antagonists, or allosteric modulators for these receptor subtypes, with a focus on mental health function or dysfunction. Technologies and approaches aimed at either well characterized receptor subtypes or understudied/orphan receptors would be of potential interest to NIMH. Examples include, but are not limited to:

    • Novel technologies and approaches to further elucidate the structure and function of GPCRs might include: high resolution molecular imaging techniques, novel crystallization strategies, novel computational modeling strategies, novel technologies and/or approaches to increase the yield of GPCR protein, etc.
    • Novel technologies to determine the dimerization and/or multimerization state of GPCRs in native neurons
    • Novel tools to identify and characterize GPCR dimers and/or multimers, such as dimer- or multimer-specific antibodies or new ways to generate such antibodies
    • Novel assays of biased GPCR signaling that can be used to identify and characterize functionally selective agonists and allosteric modulators
    • Computational approaches to structure-based design of GPCR agonists, antagonists, and allosteric modulators with superior receptor subtype or signaling specificity over existing compounds
    • Novel technologies or approaches to identify and characterize understudied and/or orphan GPCRs in the brain, such as adhesion GPCRs
    • Novel technologies and approaches to profile GPCR activity across phyla, during development, and in different brain regions/cell types. 
    • Development of methods to screen for novel GPCR interacting proteins. 

    Protection of Human Subjects: Applications with data collection plans that involve multiple respondent groups (e.g., clients/patients, therapists/providers, supervisors, administrators) should address provisions for human subject protections and consenting procedures for all participant groups, accordingly. The NIMH has published updated policies and guidance for investigators regarding human research protection and clinical research data and safety monitoring (NOT-MH-15-025). The application's Protection of Human Subjects section and data and safety monitoring plans should reflect the policies and guidance in this notice. Plans for the protection of research subjects and data and safety monitoring will be reviewed by the NIMH for consistency with NIMH and NIH policies and federal regulations.

    See Section VIII. Other Information for award authorities and regulations.

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