MECHANISMS OF ADIPOSE TISSUE FUNCTIONAL DECLINE WITH AGE - FUNCTIONAL DECLINE OF VISCERAL ADIPOSE TISSUE, B…
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ASST_NON_K00AG095479_075 · WASHINGTON UNIVERSITY, THE · Department of Health and Human Services
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- Assistance award identifier
- ASST_NON_K00AG095479_075
- FAIN
- K00AG095479
- Recipient
- WASHINGTON UNIVERSITY, THE
- Awarding agency
- Department of Health and Human Services
- Funding agency
- Department of Health and Human Services
- Assistance listing (CFDA)
- 93.866
- Total obligated
- $88,723
- Period
- Sep 29, 2025 – May 31, 2030
- Fiscal year
- 2026
- Place of performance state
- MO
- Source file
- FY2026_All_Assistance_Full_20261006.zip
Description
MECHANISMS OF ADIPOSE TISSUE FUNCTIONAL DECLINE WITH AGE - FUNCTIONAL DECLINE OF VISCERAL ADIPOSE TISSUE, BOTH IMMUNOLOGICALLY AND METABOLICALLY, CONTRIBUTES TO AGE-RELATED DISEASES. AGING INDUCES PHENOTYPIC ALTERATIONS IN IMMUNE CELLS AND ADIPOCYTES WITHIN ADIPOSE TISSUE, LEADING TO CHRONIC LOW-GRADE INFLAMMATION AND METABOLIC DYSFUNCTION INCLUDING IMPAIRED LIPOLYSIS AND GLUCOSE RESISTANCE. NOTABLY, AGED ADIPOSE TISSUE MACROPHAGES (ATMS) EXHIBIT INCREASED MITOCHONDRIAL BURDEN, ALTERED CHROMATIN ACCESSIBILITY, AND AMPLIFIED SECRETION OF INFLAMMATORY CYTOKINES, COLLECTIVELY DRIVING VISCERAL ADIPOSE DYSFUNCTION THROUGH INTERACTIONS WITH OTHER IMMUNE CELLS AND WHITE ADIPOCYTES. IN THE PRE-F99 PHASE, I DEMONSTRATED THAT GDF3, A CYTOKINE SECRETED SELECTIVELY BY ATMS, ACTIVATES THE CANONICAL SMAD2/3 PATHWAY AND SHIFTS THE CHROMATIN LANDSCAPE OF ATMS TOWARD AN INFLAMMATORY PROFILE WITH AGE. GDF3 ALSO WORSENS GLUCOSE SENSITIVITY IN OLD MICE, SUGGESTING A GDF3-MEDIATED INTERACTION BETWEEN ATMS AND ADIPOCYTE DYSFUNCTION DURING AGING. IN THE F99 PHASE, I WILL INVESTIGATE HOW THE GDF3- SMAD2/3 AXIS IMPAIRS LIPOLYSIS IN AGED ADIPOCYTES. ADIPOCYTES ARE HETEROGENEOUS AND CAN BE CLASSIFIED INTO SUBSETS BASED ON FUNCTIONALITY. AGE-RELATED IMBALANCE IN THESE SUBSETS, SUCH AS A DECLINE IN LIPOLYTIC ADIPOCYTE SUBSET, MAY IMPAIR LIPOLYSIS, LEADING TO REDUCED EXERCISE CAPACITY, DAMPENED COLD STRESS RESILIENCE, AND EXACERBATED INFLAMMATION DURING INFECTIONS IN THE ELDERLY. HOWEVER, ADIPOCYTE COMPLEXITY REMAINS LARGELY UNDERSTUDIED, PARTICULARLY IN THE CONTEXT OF AGING, DUE TO THE LACK OF ACCESSIBLE TOOLS FOR SINGLE CELL RESOLUTION ANALYSIS. I WILL CONTINUE DEVELOPING METHODS TO EXPLORE ADIPOCYTES AT THE SINGLE CELL LEVEL, AIMING TO IDENTIFY, CHARACTERIZE AND TARGET THE LIPOLYTIC ADIPOCYTE SUBSET AFFECTED BY GDF3-SMAD2/3 SIGNALING. THE PATHOPHYSIOLOGIC ROLE OF MITOCHONDRIA DURING AGING, SPECIFICALLY THE LINK BETWEEN MITOCHONDRIAL DYSFUNCTION AND CHRONIC INFLAMMATION, HAS BEEN INCREASINGLY