MOLECULAR MECHANISMS LINKING EPIGENETIC CHANGES TO LONGEVITY - PROJECT SUMMARY UNDERSTANDING MOLECULAR MECH…
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ASST_NON_R00AG065508_075 · BROWN UNIVERSITY · Department of Health and Human Services
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- Assistance award identifier
- ASST_NON_R00AG065508_075
- FAIN
- R00AG065508
- Recipient
- BROWN UNIVERSITY
- Awarding agency
- Department of Health and Human Services
- Funding agency
- Department of Health and Human Services
- Assistance listing (CFDA)
- 93.866
- Total obligated
- $846,796
- Period
- Aug 1, 2020 – Nov 30, 2025
- Fiscal year
- 2023
- Place of performance state
- RI
- Source file
- FY2023_All_Assistance_Full_20261006.zip
Description
MOLECULAR MECHANISMS LINKING EPIGENETIC CHANGES TO LONGEVITY - PROJECT SUMMARY UNDERSTANDING MOLECULAR MECHANISMS THAT GOVERN THE AGING PROCESS IS CRITICAL IN THE FACE OF THE EVER-INCREASING INCIDENCE OF AGE-RELATED DISEASES. LOSS OF EPIGENETIC REGULATION WITH AGE HAS EMERGED AS A HALLMARK OF AGING, BUT LITTLE IS KNOWN ABOUT THE MECHANISMS LINKING CHROMATIN ALTERATIONS TO LONGEVITY. RECENTLY, IN COLLABORATION WITH THE BRUNET LAB AT STANFORD UNIVERSITY, WE DEMONSTRATED THAT CHROMATIN CHANGES IN THE CAENORHABDITIS ELEGANS GERMLINE, SPECIFICALLY A DEFICIENCY IN TRIMETHYLATION OF LYSINE 4 ON HISTONE H3 (H3K4ME3) VIA THE COMPLEX PROTEINS ASSOCIATED WITH SET1 (COMPASS), INDUCE CHANGES IN EXPRESSION OF MTOR TARGETS WHICH ORCHESTRATE A METABOLIC SHIFT IN SOMATIC TISSUES TO EXTEND LIFESPAN VIA A SPECIFIC ENRICHMENT OF MONO-UNSATURATED FATTY ACIDS (MUFAS). THIS EFFECT IS MEDIATED BY THE SREBP1/SBP-1 TRANSCRIPTION FACTOR, WHICH IS ACTIVATED THROUGH COPII- MEDIATED ER-TO-GOLGI TRANSPORT. RECENT DATA IN MAMMALS HIGHLIGHTED A CRITICAL ROLE FOR CREB REGULATED TRANSCRIPTIONAL COACTIVATOR (CRTC)2 IN COPII TRAFFICKING, WHILE WE HAVE SHOWN THAT THE SOLE C. ELEGANS CRTC MODULATES AGING AND ENERGETIC METABOLISM. EXCITINGLY, MY PRELIMINARY DATA INDICATE THAT CRTC-1 SPECIFICALLY REGULATES LIFESPAN EXTENSION IN H3K4ME3-DEFICIENT ANIMALS, ESTABLISHING A NOVEL ROLE OF CRTC-1 IN THE EPIGENETIC REGULATION OF AGING. MY LONG-TERM GOAL IS TO UNDERSTAND HOW EPIGENETIC REGULATION INTEGRATES ENVIRONMENTAL AND INTERNAL SIGNALS TO INFLUENCE GENE EXPRESSION AND DOWNSTREAM CELLULAR PROCESSES TO PROMOTE LONGEVITY AND TRANSGENERATIONAL BENEFITS. THIS PROPOSAL WILL USE A COMBINATION OF GENETICS, MICROSCOPY, METABOLOMICS, AND GENOMIC APPROACHES TO UNCOVER THE MOLECULAR MECHANISMS THAT MEDIATE H3K4ME3-DEPENDENT LONGEVITY. AIM 1 WILL DEFINE THE SPATIOTEMPORAL REQUIREMENTS OF THE COMPASS CHROMATIN COMPLEX TO MEDIATE LONGEVITY AND ITS EFFECTORS SUCH AS CRTC-1, SREBP1/SBP-1 AND MTOR TARGETS. TO COMPLEMENT THESE