Key Dates

NOT-MH-22-015 - Notice of Intent to Publish a Funding Opportunity Announcement for Scalable and Systematic Neurobiology of Psychiatric and Neurodevelopmental Disorder Risk Genes: Data Resource and Administrative Coordination Center (U24 Clinical Trial Not Allowed)

National Institute of Mental Health (NIMH)

The National Institute of Mental Health (NIMH), intends to promote a new initiative by publishing a Funding Opportunity Announcement (FOA) to solicit applications to establish a group of Assay and Data Generation Centers (ADGC) as a component of the Scalable and Systematic Neurobiology of Psychiatric and Neurodevelopmental Disorder Risk Genes (SSPsyGene) Consortium. The long-term goal of SSPsyGene is to systematically characterize phenotypes, across biological scales of organization (molecular, cellular, circuit, systems/organismal), for neurodevelopmental and psychiatric disorder (NPD) risk genes. The ADGCs will be responsible for developing and carrying out high-throughput assays to characterize the central nervous system (CNS) function of selected risk genes. ADGCs will leverage scalable technologies to functionally assay null alleles of ~100-250 genes with an increased burden of loss-of-function mutations in NPDs, optimize novel assays for cellular and physiological phenotypes, and assess the scale limitations of such methods for allelic series of patient variants across large numbers of risk genes. ADGCs will work in collaboration with the SSPsyGene Data Resource and Administrative Coordination Center (DRACC; NOT-MH-22-015), which will develop methods and standards to create a harmonized cross-modality and cross-species phenotypic dataset to systematically characterize the function of NPD risk genes. This resource will be made available for broad use by the biomedical community.

This Notice is being provided to allow potential applicants sufficient time to develop meaningful collaborations and responsive projects.

The FOA is expected to be published in Winter 2022 with an expected application due date in Summer 2022.

This FOA will utilize the RM1 activity code. Details of the planned FOA are provided below.

Background

Current prioritization of genes for biological characterization does not necessarily reflect the physiological importance nor relevance of the genes to human disease. Instead, 90% of research focuses on 10% of genes in the human genome. This limited knowledge base impedes our ability to understand basic gene function and disease mechanisms despite accelerated discovery of disease genes over the past decade. One of the main bottlenecks in translating disease-associated genes into biological insight lies in the lack of scalable experimental platforms that can extend the unbiased nature of gene discovery to the discovery of biological function. Emerging technologies addressing these limitations now offer the opportunity to functionally characterize the contribution of genetic variation to complex common diseases, such as neurodevelopmental and psychiatric disorders (NPDs; e.g., autism and schizophrenia). This can be achieved with systematic and coordinated assays that capture the genetic and phenotypic space at a greater scale and expanded breadth. Such an approach would provide a collaborative and efficient framework for delineating biology in order to generate a standardized, experimentally derived, functional catalog of NPD risk genes. This basic neurobiology resource would provide a fertile foundation for future studies into disease mechanisms. The NIMH is thus initiating a new program, the Scalable and Systematic Neurobiology of Psychiatric and Neurodevelopmental Disorder Risk Genes (SSPsyGene) Consortium, with the goal of developing a comprehensive phenotypic catalog across biological scales for genes associated with NPDs. The SSPsyGene Consortium will support multidisciplinary research centers to optimize and implement systematic and scalable approaches for characterizing the developmental, molecular, cellular, systems, and organismal CNS function of NPD risk genes. The resulting phenotypic data will be integrated across modalities, levels of organization, and genes, to create a harmonized, integrated knowledge base that forms a solid foundation of data needed for future efforts into potential shared and unique disease mechanisms.

The SSPsyGene Consortium will be made up of two highly interactive components with complementary roles as follows:

• Assay and Data Generation Centers (ADGC) to engineer comparable null alleles across experimental systems, to assess and catalog the resulting molecular and cellular phenotypes, pilot these assays for a select allelic series of patient variants, and support optimization of innovative assays of CNS function.
• Data Resource and Administrative Coordinating Center (DRACC) (Companion, see NOT-MH-22-015) to develop a rigorous data-driven framework for prioritizing NPDs risk genes; receive, integrate, annotate, harmonize, and present data for the consortium and public use; and provide logistical support for the consortium.

Assays will include informative, CNS-relevant phenotypes across scales of biological organization from molecular and cellular to physiological and organismal, using experimental systems (e.g., human cell-based models, model organisms, ex vivo preparations) that are reproducible and scalable for hundreds of genes, are informative of human neurobiology, and align with NIMH priorities. While the long-term goal of SSPsyGene is to reach biological saturation with respect to NPD risk genes, the target for the initial phase of the initiative is at least 100-250 protein-coding genes. Development of a scientifically rigorous gene prioritization schema will be led by the DRACC with input from all members of the SSPsyGene Consortium, the NIMH, and external advisors. The main focus of this phase of SSPsyGene will be on assaying null alleles to gain insights into basic gene function, however to address the ultimate goal of understanding the functional impact of disease-associated genetic variation, the consortium will also pilot established SSPsyGene assays against an allelic series from a small subset of NPD risk genes.

Research Objectives

The goal of the ADGCs is to optimize and implement scalable and systematic assays to interrogate the neurobiological functions of NPD risk genes. It is anticipated that proposed allele generation methods and assays will be developed enough to begin production-scale implementation of assays within the first year. The ADGCs will form a collaborative network, working with the SSPsyGene DRACC to perform complementary assays on a common set of genes and to develop data, metadata, and methods standards to ensure results are comparable, reproducible, and to enable data integration.

Anticipated research objectives include:

1. Perform a systematic functional assessment of ~100-250 risk genes (as prioritized through consortium discussions) using scalable screening platforms to assay neurobiological function. The ADGCs will obtain or generate null alleles of SSPsyGene Consortium-selected NPD risk genes in their proposed experimental systems. The ADGCs will then conduct systematic phenotypic analysis of the alleles in proposed assays in one or more of the following high priority assay areas:
   • Molecular assays: Unbiased, comprehensive phenotyping approaches using large-scale molecular approaches such as genomics (e.g., gene expression, transcriptional and translational regulation, DNA methylation, chromatin state, and conformation) or other omic-scale profiling (e.g., proteomics, metabolomics).
   • Cellular, circuit, or systems/organismal assays (e.g., signaling, synaptic activity, neural dynamics, morphology). Assays of interest include, but are not limited to:
     • Protein-level characterization (e.g. structural and biophysical properties, translational modifications, endogenous protein dynamics)
     • Molecular interactions and pathways (e.g., signal transduction, neurotransmitter-receptor interactions, protein-protein interactions)
     • Inter-cellular functional interaction (e.g., synaptic activity measures using optical physiology)
     • High resolution neural activity assays (e.g., multi-electrode array activity profiling, calcium imaging of population dynamics)
     • High content imaging assays (cellular morphology, structural plasticity)

• • Optional: Develop and optimize novel pilot assays. Projects for assay development should emphasize the design and validation of creative approaches to assay biological processes that have the potential to broadly inform our understanding of NPD risk gene function in the CNS.

2. Develop methods to ensure comparability and reproducibility, including developing metrics and quality standards; standardize allele and assay validations; working with the consortium to establish a common structured controlled vocabulary and specifications for data and metadata.
3. Actively contribute to the SSPsyGene Consortium, data sharing, and outreach efforts, including collaborating with the consortium to establish gene prioritization schema, taking part in consortium meetings, and participating in consortium activities and projects.

Applications are not being solicited at this time.

Please direct all inquiries to:

Jamie Driscoll
National Institute of Mental Health (NIMH)
301-443-5288
[email protected]

Rebecca Beer, PhD
National Institute of Mental Health (NIMH)
301-402-3969
[email protected]