ROLE OF SELECTIVE AUTOPHAGY IN AGING AND NEURODEGENERATION: A SMALL MOLECULE APPROACH - PROJECT SUMMARY/ABS…

Assistance award details

Assistance award identifier

ASST_NON_R00AG080109_075

FAIN

R00AG080109

Recipient

UNIVERSITY OF ARIZONA

Awarding agency

Department of Health and Human Services

Funding agency

Department of Health and Human Services

Assistance listing (CFDA)

93.866

Total obligated

$249,096

Period

Feb 15, 2023 – Feb 28, 2029

Fiscal year

2026

Place of performance state

AZ

Source file

FY2026_All_Assistance_Full_20261006.zip

Description

ROLE OF SELECTIVE AUTOPHAGY IN AGING AND NEURODEGENERATION: A SMALL MOLECULE APPROACH - PROJECT SUMMARY/ABSTRACT A HYPOTHESIS OF AGING IS THAT THE ACCUMULATION OF CELLULAR DAMAGE CAN LEAD TO TISSUE MALFUNCTION AND ORGANISMAL DETERIORATION. A KEY MECHANISM FOR MAINTAINING CELLULAR HOMEOSTASIS AND PRESERVING CELL FUNCTION IS AUTOPHAGY, A HYDROLYTIC CELLULAR RECYCLING PROCESS WHEREBY CYTOSOLIC MATERIALS, REFERRED TO AS CARGO, INCLUDING LIPID DROPLETS (LDS) AND DAMAGED PROTEINS, ARE DEGRADED IN THE LYSOSOME. IN TURN, ABERRATIONS IN AUTOPHAGY CAN RESULT IN THE ACCUMULATION OF DIFFERENT TOXIC CYTOSOLIC CONTENTS, WHICH IS A MOLECULAR SIGNATURE OF MANY AGE-RELATED DISORDERS, INCLUDING NEURODEGENERATION. WHILE THERE IS A PROMINENT FUNCTIONAL LINK BETWEEN AUTOPHAGY, AGING AND DISEASES, THE MOLECULAR MECHANISMS THAT CAUSE THE AGE-DEPENDENT DECREASES IN AUTOPHAGY REMAIN UNCLEAR. NOTABLY, AUTOPHAGY CAN ALSO SELECTIVELY RECRUIT ONE TYPE OF MOLECULE FOR DEGRADATION. RECENT STUDIES SUPPORT THE HYPOTHESIS THAT SELECTIVE AUTOPHAGY PLAYS A CRUCIAL ROLE IN COMBATING CHRONIC DISEASES. SEVERAL HUMAN BRAIN POST-MORTEM STUDIES HAVE UNCOVERED LIPID SPECIES THAT ACCUMULATE IN BRAINS AFFECTED BY ALZHEIMER’S DISEASE (AD), POSSIBLY IMPEDING NEURONAL FUNCTION AND THEREBY CONTRIBUTING TO NEURODEGENERATION. THEREFORE, DISCOVERING DIFFERENT INTERVENTIONS THAT CAN BE USED TO AFFECT LIPOPHAGY (LD TURNOVER) SELECTIVELY MAY BE IDEAL FOR TACKLING LIPIDOTOXICITY-LINKED AD. HOWEVER, SUCH PHARMACOLOGICAL OR GENETIC TOOLS ARE CURRENTLY UNAVAILABLE. FURTHERMORE, SELECTIVE CELLULAR FACTORS THAT CAN FACILITATE LD RECRUITMENT FOR LIPOPHAGY REMAIN UNKNOWN. IN THIS PROPOSAL, I AIM TO ADDRESS THESE GREATER NEEDS IN UNDERSTANDING THE REGULATORY MECHANISMS OF LIPOPHAGY AND ITS FUNCTION RELEVANT TO AGING AND NEURODEGENERATIVE DISORDERS. OUR LAB RECENTLY PERFORMED A CELLULAR LD CLEARANCE HIGH-THROUGHPUT SCREEN TO IDENTIFY SMALL MOLECULES AND PATHWAYS THAT INDUCE SELECTIVE LIPID CLEARING AUTOPHAGY FOR SLOWING AGE-R