Project Grant K99AG086525

BALANCING CELLULAR REPAIR AND REGENERATION IN AGING AND DISEASE - PROJECT SUMMARY/ABSTRACT BACKGROUND: AGING IS AN INCREDIBLY PLASTIC PROCESS THAT IS DICTATED BY COORDINATED REPAIR AND REGENERATIVE MECHANISMS. LOSS OF THIS COORDINATION MARKS THE START OF TISSUE DECLINE AND AGING, THEREBY INCREASING DISEASE SUSCEPTIBILITY. ALARMINGLY, AGE-DEPENDENT DISEASES ARE DISPROPORTIONATELY RISING IN YOUNG AGE GROUPS WITHOUT KNOWN CAUSE. EARLY-AGE ONSET COLORECTAL CANCER (EAO CRC) IS A PRIME EXAMPLE, WHICH AFRICAN AMERICANS EXPERIENCE THE HIGHEST DISEASE BURDEN. RATIONALE: PREVIOUSLY, WE DISCOVERED A NOVEL HEDGEHOG (HH)-DEPENDENT MECHANISM THAT BALANCES CELLULAR REPAIR AND REGENERATION TO SUSTAIN HEALTHY TISSUE AGING. SPECIFICALLY, WE IDENTIFIED THE HH EFFECTOR PATCHED (PTC) AS A CRITICAL SWITCH FOR BALANCING AUTOPHAGY-BASED CELLULAR REPAIR AND HH-DEPENDENT REGENERATIVE PROLIFERATION. IMPORTANTLY, LOSS OF PTC FUNCTION DRIVES ACCELERATED CELLULAR AGING. HYPOTHESIS: WE PROPOSE THAT THE CELLS ARE AGING RAPIDLY RELATIVE TO CHRONOLOGICAL AGE, DUE TO THE LOSS OF THIS HH-DEPENDENT COORDINATION OF AUTOPHAGY AND PROLIFERATION. WE PREDICT FACTORS THAT PROMOTE ABERRANT HH SIGNALING PREDISPOSE INDIVIDUALS TO EAO CRC ONSET. SPECIFIC AIMS: TO TEST THIS HYPOTHESIS, I WILL DELINEATE THE MECHANISM OF HH SIGNALING IN BALANCING AUTOPHAGY AND PROLIFERATION TO PRESERVE CELLULAR AGING (AIM 1); DEFINE THE HH-DEPENDENT TRANSCRIPTOME DURING AGING, WITH A PARTICULAR INTEREST IN IDENTIFYING GENES THAT ARE DYSREGULATED IN CANCERS IMPACTING AFRICAN AMERICANS (AIM 2); AND FUNCTIONALLY TEST THE INTERSECTION OF HH SIGNALING AND GENETIC DETERMINANTS OF CANCER DISPARITIES USING BOTH THE DROSOPHILA INTESTINES MODEL AND PATIENT-DERIVED COLON ORGANOIDS (AIM 3). THIS STUDY WILL PRECISELY DEFINE FUNDAMENTAL MECHANISMS AND AGING-DEPENDENT CELLULAR MARKERS THAT ARE APPLICABLE TO DISEASES IMPACTING AFRICAN AMERICAN COMMUNITIES. THE CULMINATION OF THIS INVESTIGATION WILL HONE THE REQUIRED KNOWLEDGE, TECHNICAL SKILLSETS, AND PROFESSIONAL NETWORKS TO SUCCESSFULLY LAUNCH MY INDEPENDENT RESEARCH PROGRAM, FOCUSED ON ELUCIDATING REGULATORS OF THE AUTOPHAGY-PROLIFERATION BALANCE TO REDUCE AGING-RELATED DISEASE DISPARITIES.