NIH funding opportunity – Phenotypic and Functional Studies on FOXO3 Human Longevity Variants to Inform Potential Therapeutic Target Identification Research (R01)

April 6, 2015 by School of Medicine Webmaster   |   Leave a Comment

The focus of this FOA is on in vivo human studies, and in vitro studies on human cells or tissues, aimed at potential identification of therapeutic targets or and/or testing of interventions for healthy aging. Potential therapeutic targets include FOXO3 itself and upstream and downstream regulators in pathways mediated by FOXO3. The range of research areas of interest in this FOA includes studies that: 1) examine in vivo phenotypic effects of human FOXO3 variants, and/or 2) elucidate effects of these variants on cellular functions and the pathways that mediate them, and/or 3) identify and evaluate candidate therapeutic targets (e.g., target validation studies, testing of candidate compounds) for potential interventions based on FOXO3 functional pathways.

Examples of potential research strategies to address the research objectives include, but are not limited to:

  • Secondary analyses of human cohort data and analyses of stored bio specimens from populations in which FOXO3 genotypic information is available or obtainable.
  • De novo human physiologic studies comparing individuals with FOXO3 longevity variants with those with other FOXO3 alleles, including discordant twin studies.
  • In vitro functional studies comparing cells with FOXO3 longevity variants and donors with other FOXO3 alleles, using cells from differing donors or gene editing methods.
  • Studies on differing tissues or cell types, including studies on iPSCs or other methods.
  • High-throughput assays for compounds that produce similar cellular functional effects to those of FOXO3 longevity variants.

For all the above, consideration of potential differences in phenotypic and functional effects to age and tissue differences, and to gene-environmental actions (e.g., response to stressors) is encouraged.

Research projects of interest include, but are not limited to:

  • Phenotypic comparisons between individuals with and without FOXO3 longevity variants using data from epidemiologic studies to examine specific effects of the FOXO3 variants on physiology and health  across the life span, including identification of possible intermediate phenotypes or longevity “endophenotypes”.
  • Characterization of differential expression patterns of FOXO3 transcripts in individuals from existing cohorts, as a function of age, cell/tissue type and their relationship to aging outcomes.
    • Analysis of functional polymorphisms among the FOXO3 longevity variants that may regulate gene expression, alternative splicing, mRNA stabilization, protein translation, post translational modifications of the protein,  and nuclear localization and cytoplasmic translocation of the protein that may contribute to health span or longevity.
    • Human in vitro studies using cells from individuals to elucidate effects on biological pathways of FOXO3 longevity variants. Studies in different human cell types and a variety of physiologic/cellular functions are encouraged to identify tissue/cell-specific action(s) of FOXO3 longevity variants.
    • Elucidation of functional gene networks involved in mediating FOXO3 protective effects through integrative analyses of genomics, proteomics, and metabolomics data from mammalian models expressing the FOXO variants or in genetically edited human cells.
    • Studies of effects of compounds engaging possible therapeutic target(s) suggested by phenotypic or functional FOXO3 studies, with regard to the degree to which their effects mimic those of FOXO3 longevity variants. In vitro studies on human cells and laboratory animal model studies are of interest, as well as (where ethical and feasible) in vivo human studies on currently approved drugs.
  • Projects involving whole genome sequencing of new or existing cohorts are outside the scope of this FOA. However, targeted resequencing on a limited sample set in an existing cohort could be supported by this FOA.

For ancillary studies using data from established cohort studies, applicants are responsible for adhering to the individual study policies governing ancillary projects and access to clinical trials data and/or biorepository samples.

Deadlines:  standard dates apply



Filed Under: Funding Opportunities



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