Project Grant R01AG086058

DISSECTING THE AGING SKELETAL STEM CELL NICHE - PROJECT SUMMARY MAINTENANCE, REMODELING, AND REPAIR OF THE ADULT BODY IS MEDIATED BY MULTIPOTENT STEM CELLS THAT GIVE RISE TO A VARIETY OF CELL TYPES THAT COMPRISE THE TISSUE IN WHICH THEY RESIDE. DURING AGING, THERE IS A DECLINE IN HOMEOSTATIC AND REGENERATIVE CAPACITY LEADING TO PROGRESSIVE DEGENERATION OF THE STRUCTURE AND FUNCTION OF VITAL ORGANS. IN PARTICULAR, MUSCULOSKELETAL DEGENERATION IS COMMON IN THE ELDERLY AND LEADS TO INCREASED FRACTURE RISK AND REDUCED EFFICIENCY OF FRACTURE REPAIR THAT DRASTICALLY DECREASES QUALITY OF LIFE. OUR PREVIOUS STUDIES SHOWED THAT AN AGE-ASSOCIATED INCREASE IN CHRONIC, LOW-GRADE INFLAMMATION IS THE MAIN CAUSE OF SKELETAL STEM AND PROGENITOR CELL (SSPCS) DYSFUNCTION. THUS, WE HYPOTHESIZE THAT REDUCING PRO-INFLAMMATORY SIGNALS AND ENHANCING ANTI- INFLAMMATORY ACTIVITY WILL RESCUE SSPC NUMBER AND OSTEOGENIC FUNCTION IN AGED INDIVIDUALS. TO INVESTIGATE THIS, WE WILL FIRST PRECISELY DEFINE THE MOLECULAR MECHANISMS REGULATING THE INFLAMMATORY RESPONSE IN SSPCS, AND THE ROLE OF ANTI-INFLAMMATORY FACTORS IN THE RESOLUTION OF INFLAMMATION. WE WILL DETERMINE HOW THESE MECHANISMS AND THE INTERACTION BETWEEN OPPOSING PRO- AND ANTI- INFLAMMATORY SIGNALS IS AFFECTED BY AGING. THESE EXPERIMENTS WILL GENERATE INSIGHTS INTO THE ELEMENTS DRIVING BONE DEGENERATION AND IDENTIFY THERAPEUTIC TARGETS TO IMPROVE BONE HEALTH AND FRACTURE REPAIR IN ELDERLY PATIENTS. OUR STRONG PRELIMINARY EXPERIMENTS ALSO IDENTIFIED TWO PRIME SUSPECTS INVOLVED IN SSPC DETERIORATION DURING AGING. WE WILL PERFORM GAIN AND LOSS OF FUNCTION EXPERIMENTS IN SSPCS TO ELUCIDATE THEIR SPECIFIC ROLE IN THE CONTROL OF STEM CELL SELF-RENEWAL AND DIFFERENTIATION. AS MANIPULATION OF THESE FACTORS CAN AFFECT THE EXTRACELLULAR INFLAMMATORY MILIEU, WE WILL USE SINGLE-CELL RNA-SEQUENCING TO DETERMINE THEIR CELL-INTRINSIC FUNCTION IN SSPCS AND ALSO THEIR INFLUENCE ON DEFINED POPULATIONS WITHIN THE LOCAL NICHE. FINALLY, WE WILL MANIPULATE CANDIDATE EXPRESSION FOLLOWING INJURY IN AGED ANIMALS TO ASSESS THEIR ABILITY TO RESCUE STEM CELL REGENERATIVE CAPACITY AND IMPROVE BONE HEALING.