THE ROLE OF GLIA IN MONITORING NEURONAL PROTEOSTASIS IN AGING - ALTHOUGH GLIA, THE NON-NEURONAL CELLS OF TH…

Assistance award details

Assistance award identifier

ASST_NON_K00AG068343_075

FAIN

K00AG068343

Recipient

NEW YORK UNIVERSITY

Awarding agency

Department of Health and Human Services

Funding agency

Department of Health and Human Services

Assistance listing (CFDA)

93.866

Total obligated

$337,755

Period

Sep 1, 2020 – Jul 31, 2026

Fiscal year

2022

Place of performance state

NY

Source file

FY2022_All_Assistance_Full_20261006.zip

Description

THE ROLE OF GLIA IN MONITORING NEURONAL PROTEOSTASIS IN AGING - ALTHOUGH GLIA, THE NON-NEURONAL CELLS OF THE BRAIN, ARE INCREASINGLY IMPLICATED IN AGING AND NEURODEGENERATIVE DISEASE, WE KNOW VERY LITTLE ABOUT HOW THESE CELLS INTERACT WITH NEURONS DURING AGING. NEURODEGENERATIVE DISEASES, LIKE ALZHEIMER'S DISEASE, ARE CHARACTERIZED BY AGGREGATED MISFOLDED PROTEINS, WHICH CAN CAUSE CELL DEATH AND DYSFUNCTION. CELLS HAVE DEVELOPED SYSTEMS TO DETECT AND FIX THESE PROBLEMS IN A CELLULAR COMPARTMENT-SPECIFIC MANNER; HOWEVER, THESE RESPONSES TO PROTEIN MISFOLDING START TO FAIL AS ORGANISMS AGE. WE HAVE PREVIOUSLY SHOWN THAT NEURONS SEND OUT SIGNALS TO ALERT OTHER CELLS WHEN THEY EXPERIENCE PROTEIN TOXICITY AND STRESS, WHICH COULD BE A CLUE TOWARDS HOW THE BODY COULD NATURALLY FIX PROTEIN MISFOLDING IN NEURODEGENERATIVE DISEASE. HOWEVER, NO ONE HAS YET INVESTIGATED HOW GLIA RESPOND TO PROTEIN STRESS IN THE CYTOSOLIC COMPARTMENT OF THE CELL. OUR LABORATORY PREVIOUSLY SHOWED THAT NEURONAL OVER-EXPRESSION OF THE MAIN REGULATOR OF THE CYTOSOLIC UNFOLDED PROTEIN RESPONSE, HEAT SHOCK FACTOR 1 (HSF-1), IS ABLE TO SIGNAL TO DISTAL CELLS TO INCREASE HEALTHY PROTEIN FOLDING EFFECTORS AND HELP ORGANISMS LIVE LONGER. HERE, WE PROPOSE THAT GLIAL CELLS CAN ALSO SIGNAL THE HEAT SHOCK RESPONSE TO COORDINATE A PAN-ORGANISMAL RESPONSE AND PROMOTE LONGEVITY (AIM 1). OUR APPROACH IN THIS AIM TAKES ADVANTAGE OF THE GENETIC TRACTABILITY, SHORT LIFESPAN, AND SIMPLE IMAGING OF THE MODEL ORGANISM, C. ELEGANS, TO STUDY NON-CELL AUTONOMOUS SIGNALING BETWEEN TISSUES IN AGING. TO FURTHER ADDRESS THE ROLE OF GLIA IN RESCUING NEURONS FROM PROTEIN TOXICITY, WE WILL EXAMINE MICROGLIA IN THE MAMMALIAN BRAIN. HERE, WE ASK WHETHER HEALTHY MICROGLIA CAN RESCUE NEURONS STRESSED WITH TAU PROTEIN MISFOLDING, WHICH IS A COMMON FEATURE OF ALZHEIMER'S DISEASE AND OTHER DEMENTIAS, AND WHETHER AGED MICROGLIA MIGHT BE DEFECTIVE IN THEIR AID TO NEURONS. WE WILL ASSESS HOW MICROGLIA SURVEIL THE INTERNAL PROTEIN HOMEOS