Limited Competition: Multi-scale Molecular Profiling of Brains from Psychiatric Cohorts (R01)
Department of Health and Human Services
National Institutes of Health
Research Objectives and Scope
The goal of this limited competition is to generate, integrate, and analyze multi-modal molecular profiles (e.g., genomic, transcriptomic, epigenomic, proteomic, etc.) from multiple brain regions and cell types/subtypes in healthy and diseased human brains. Generation of multi-omic profiles will allow direct integration of genome-wide information across multiple molecular scales for a given cell-type or brain region, or developmental period, controlling for major confounds. Such integrated multi-omic molecular datasets should be leveraged to build robust and informative molecular models of disease through approaches that gain systems-level understanding of molecular interactions underlying the complex genetic etiology of psychiatric disorders. These datasets will facilitate evaluation of novel brain tissue-specific exons, splicing variations, transcript and protein isoforms, RNA editing, gene regulatory elements, and epigenetic markings. Integration of these multi-modal molecular maps with other large-scale, ongoing genomic studies (e.g, Brainspan, 1000 Genomes, CommonMind, GENCODE,REMC, IHEC, Psychiatric Genomic Consortium, and GTEx) will allow researchers to use molecular phenotypes to address compelling scientific questions regarding the molecular mechanisms associated with psychiatric disorders.
This limited competition is open to the Common Mind Consortium and the PsychENCODE Consortium investigators who, by virtue of their consortia involvement, have access to existing large, high quality, phenotypically well-characterized human brain collections. More importantly, the consortium members will be able to build upon existing data generation efforts within the consortia, leveraging data coordination and analytic infrastructure that has already been established. For more information about eligibility, see Section III.
The collective goals of these consortia are to map the landscape of human brain-specific, genomic regulatory elements and identify their role in brain function and dysfunction in psychiatric disorders. Thus far, analyses in these consortia have been limited to RNA-Seq (transcriptome) and Chip-Seq analyses on fewer brain regions (primarily prefrontal cortex) to map functional regulatory elements. This FOA seeks to expand upon the ongoing efforts in these consortia and solicits applications to conduct comprehensive assessments of multi-omic molecular profiles across brain regions and cell-types using state-of-the-art, unbiased genomic, and computational approaches. Comprehensive assessments could include generating, integrating, and analyzing different types of omic data (e.g., genomic, transcriptomic, epigenomic, proteomic, epitranscriptomic, chromatin architecture, etc.) in healthy and diseased brains from the same cohort of brain collections that are currently being assessed by the consortia, covering two or more psychiatric phenotypes. The scope of the projects should be complementary to, rather than duplicative of, those currently supported by the consortia.
Applicants are strongly encouraged to include: 1) assessments of at least two key developmental time periods relevant to psychiatric and neurodevelopmental disorders, such as mid-fetal gestation, postnatal, early childhood, adolescence age groups, and 2) assessments of different cell types/subtypes (e.g., different neuronal and glial cell types) or cell lineages across multiple brain regions which are of relevance to psychiatric disorders. Brain regions of interest for such analyses (where data is currently limited) include nucleus accumbens, caudate-putamen, striatum, hippocampus, amygdala, thalamus, neuromodulatory regions, anterior singulate cortex, subgenual cingulate cortex, etc. Building a knowledge base of multiple domains of molecular information on a given set of samples/individuals with spatial and temporal resolution would allow discovery of regulatory mechanisms and molecular networks that drive critical neurobiological processes involved in brain development and function, as well as, dysfunction in psychiatric disorders.
All applications supported under this FOA and the companion FOA are expected to leverage existing large well-curated human brain collections represented in the PsychENCODE Consortium, and the Common Mind Consortium to generate multi-omic molecular profiles in healthy and diseased brain samples. Applications are expected to also include a comprehensive plan for rapid and timely release of resulting data to the wider scientific community through existing public data repositories, consistent with achieving the goals of this program.
This FOA focuses on generating multi-omic data from across brain regions, cell subtypes, and key developmental time periods relevant to psychiatric disorders. Areas of interest include, but are not limited to:
- Generation of high-depth, whole genome sequencing data to allow for improved evaluation of various genetic alterations (e.g., single nucleotide variants, copy number variants, structural variants, etc.).
- Generation of comprehensive, high resolution human brain region/cell type and age-specific maps of different classes of functional RNA molecules (e.g., long non-coding RNAs, microRNAs, coding regions, etc.), DNA methylation, chromatin accessibility and regulatory elements (e.g., promoters, enhancers, silencers, insulators, transcription factor binding sites, etc.).
- Identification of human brain region/cell type and age-specific splicing, exon/intron junctions, transcript and protein isoforms, allele-specific expression, quantitative trait loci, mitochondrial DNA variations that are differentially represented in diseased brains compared to healthy control brains to identify epigenomic and transcriptional regulatory mechanisms that are relevant to neuropsychiatric disorders.
- Generation of human brain region/cell type and age-specific map of RNA modifications (e.g., differential distribution and frequency of RNA editing sites) in diseased and healthy control brains.
- Generation of brain region/cell type-specific proteome data from at least two brain regions in diseased and healthy control brains.
- Generation of comprehensive brain region/cell type and age-specific genome-wide maps of chromatin states, chromatin conformation, and chromatin interactions that connect genes and transcriptional regulatory regions affecting down-stream gene expression in the context of psychiatric disorders.
- Integration of these newly generated multi-omic datasets, from diseased and healthy control brains, with large-scale genomic resources such as Brainspan, 1000 Genomes,CommonMind, GENCODE, REMC, IHEC, Psychiatric Genomic Consortium, and GTEx for the identification of cell-type and age-specific gene regulatory mechanisms and molecular networks associated with psychiatric disorders.
- Development of comprehensive molecular models of disease using systems biology approaches.
Applicants are encouraged to consult with the Scientific/Research Contact well in advance of the application due date, to discuss the structure of the collaborations, and research topics of interest for alignment of their proposed work with the NIMH Program and FOA objectives.
|Posted Date:||Sep 1, 2015|
|Creation Date:||Sep 1, 2015|
|Original Closing Date for Applications:||Nov 3, 2015|
|Current Closing Date for Applications:||Nov 3, 2015|
|Archive Date:||Dec 4, 2015|
|Estimated Total Program Funding:||$3,000,000|
Others (see text field entitled “Additional Information on Eligibility” for clarification)
|Additional Information on Eligibility:||Other Eligible Applicants include the following: Non-domestic (non-U.S.) Entities (Foreign Organizations); This FOA is limited to the awardees of the PsychENCODE Consortium and Common Mind Consortium|
|Agency Name:||National Institutes of Health|
|Description:||The purpose of this limited competition Funding Opportunity Announcement (FOA) and the companion FOA is to seek applications to explore and establish a comprehensive landscape of multi-modal molecular alterations across brain regions, leveraging existing human brain collections that include the brains of patients with psychiatric disorders, with the goal of developing molecular models of those disorders.This limited competition is open to the Common Mind Consortium and the PsychENCODE Consortium investigators who have access to existing large, high quality, and phenotypically well-characterized brain collections.|
|Link to Additional Information:||http://grants.nih.gov/grants/guide/rfa-files/RFA-MH-16-235.html|