REVERSING SKELETAL AGING BY RESTORING FUNCTIONAL SKELETAL STEM CELL DIVERSITY - ADVANCING AGE IS TIGHTLY LI…
Federal financial assistance recorded from USAspending. This is not a procurement contract.
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ASST_NON_R00AG066963_075 · UNIVERSITY OF CALIFORNIA, DAVIS · Department of Health and Human Services
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- Assistance award identifier
- ASST_NON_R00AG066963_075
- FAIN
- R00AG066963
- Recipient
- UNIVERSITY OF CALIFORNIA, DAVIS
- Awarding agency
- Department of Health and Human Services
- Funding agency
- Department of Health and Human Services
- Assistance listing (CFDA)
- 93.866
- Total obligated
- $773,746
- Period
- Apr 1, 2021 – Dec 31, 2025
- Fiscal year
- 2023
- Place of performance state
- CA
- Source file
- FY2023_All_Assistance_Full_20261006.zip
Description
REVERSING SKELETAL AGING BY RESTORING FUNCTIONAL SKELETAL STEM CELL DIVERSITY - ADVANCING AGE IS TIGHTLY LINKED TO THE INCREASING GLOBAL INCIDENCE OF SKELETAL DISEASES. OSTEOPOROSIS POSES A MAJOR PUBLIC HEALTH THREAT FOR OVER 54 MILLION AMERICANS AS IT IS INTERRELATED WITH HIGH FRACTURE RATES. OSTEOPOROSIS RELATED HIP FRACTURES ARE INVARIABLY ASSOCIATED WITH SIGNIFICANT MORBIDITY AND STRIKINGLY, A 58% MORTALITY RATE IN THE ELDERLY WITHIN THE FIRST YEAR OF INJURY. THIS PROBLEM IS COMPOUNDED BY A LACK OF EFFICIENT PREVENTIVE AND MEDICAL THERAPIES FOR AGE-RELATED BONE DISEASE FREE OF MAJOR SIDE EFFECTS. RECENT STUDIES HAVE REVEALED ADULT STEM CELL POPULATIONS WITHIN BONE THAT COULD BE POTENTIALLY TARGETED AS A REGENERATIVE SOURCE TO MAINTAIN AND RESTORE SKELETAL HEALTH. HOWEVER, BREAKTHROUGHS IN STEM CELL BASED-REGENERATIVE STRATEGIES HAVE BEEN HAMPERED BY THE INABILITY TO ISOLATE BONA FIDE STEM CELL POPULATIONS. OUR GROUP HAS HELPED DELINEATE HIGHLY PURIFIED SKELETAL STEM CELL (SSC) LINEAGES CRUCIAL FOR MAINTAINING NORMAL BONE HOMEOSTASIS AND REGENERATION FOLLOWING INJURY. MY LATEST RESULTS SUGGEST THAT AGING SHIFTS LINEAGE DETERMINATION OF STEM CELLS TRIGGERING ALTERED NICHE DYNAMICS THEREBY CONTRIBUTING TO A DECLINE OF REGENERATIVE CAPACITY AND PROVIDING A RATIONALE THAT SKELETAL AGING IS CAUSED BY SSC DYSFUNCTION. THE INITIAL FINDINGS OF THIS PROPOSAL PROVIDE EVIDENCE FOR THE EXISTENCE OF MULTIPLE SSC SUBTYPES (SSC DIVERSITY) PRESENT IN LIMB LONG BONES. TRANSCRIPTOMIC ANALYSIS AT THE SINGLE-CELL LEVEL SHOWS THAT SSCS UNDERGO AGING-INDUCED MOLECULAR AND COMPOSITIONAL CHANGES COINCIDING WITH FUNCTIONAL HETEROGENEITY. I HAVE IDENTIFIED WNT1 INDUCIBLE SIGNALING PATHWAY PROTEIN 2 (WISP2) THAT IS SPECIFICALLY UPREGULATED IN THE AGED SSC LINEAGE. WISP2 SIGNIFICANTLY IMPAIRS BONE FORMATION WHEN APPLIED TO SSC IN VITRO OR FRACTURES OF YOUNG MICE IN VIVO. AIM1 HAS DETERMINED THE ROLE OF AGE-RELATED CHANGES IN SSC DIVERSITY INCLUDING THE RELATIVE PROPORTION OF SSC SUBTYPES AN