EPIGENETIC REPROGRAMMING TO COUNTERACT NEURONAL AGING AND DEGENERATION - PROJECT SUMMARY/ABSTRACT THE AGING…
Federal financial assistance recorded from USAspending. This is not a procurement contract.
Assistance award details
- Assistance award identifier
- ASST_NON_R00AG068303_075
- FAIN
- R00AG068303
- Recipient
- SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
- Awarding agency
- Department of Health and Human Services
- Funding agency
- Department of Health and Human Services
- Assistance listing (CFDA)
- 93.866
- Total obligated
- $742,017
- Period
- Aug 1, 2020 – Jan 31, 2027
- Fiscal year
- 2024
- Place of performance state
- CA
- Source file
- FY2024_All_Assistance_Full_20261006.zip
Description
EPIGENETIC REPROGRAMMING TO COUNTERACT NEURONAL AGING AND DEGENERATION - PROJECT SUMMARY/ABSTRACT THE AGING BRAIN IS INCREASINGLY SUSCEPTIBLE TO COGNITIVE DECLINE AND DEMENTIA. ALZHEIMERâS DISEASE (AD), A MAIN FORM OF DEMENTIA, IS AN EXTREME, PATHOLOGICAL MANIFESTATION OF BRAIN AGING. HOWEVER, THE ETIOLOGY AND PATHOGENESIS OF AD ARE NOT WELL UNDERSTOOD, CAUSING THE DEARTH OF EFFECTIVE TREATMENTS. MOUNTING EVIDENCE HAS IMPLICATED EPIGENETIC CHANGES, SUCH AS DNA METHYLATION AND HISTONE ACETYLATION, IN NEURONAL AGING AND DEGENERATION, RAISING THE HYPOTHESIS THAT RESETTING THESE EPIGENETIC CHANGES AND RESTORING A YOUTHFUL EPIGENOME MAY INCREASE NEUROPLASTICITY AND FORESTALL DISEASE. WE HAVE RECENTLY DISCOVERED THAT EPIGENETIC REPROGRAMMING BY COEXPRESSION OF THREE YAMANAKA FACTORS, OCT4, SOX2, AND KLF4 (OSK), CAN INDUCE AXON REGENERATION IN RETINAL GANGLION CELLS (RGCS), A TYPE OF CENTRAL NERVOUS SYSTEM (CNS) NEURON, AFTER ACUTE INJURY. FURTHERMORE, OSK EXPRESSION IN RGCS OF OLD MICE REVERSED AGING-ASSOCIATED TRANSCRIPTOME CHANGES, RESET THE DNA METHYLATION AGE OF THE CELLS, AND RESTORED VISION TO A LEVEL SIMILAR TO YOUNG MICE, SUGGESTING NEURONAL REJUVENATION. IMPORTANTLY, CELL CYCLE, CELL IDENTITY, AND INTRINSIC ELECTROPHYSIOLOGICAL PROPERTIES OF POSTMITOTIC NEURONS WERE NOT AFFECTED BY OSK REPROGRAMMING. IN THIS PROPOSAL, I SEEK TO IDENTIFY THE EPIGENETIC MECHANISMS THAT UNDERLIE OSK-MEDIATED AXON REGENERATION (AIM 1), DETERMINE WHETHER EPIGENETIC REPROGRAMMING IN BRAIN NEURONS REVERSES AGE-ASSOCIATED COGNITIVE DECLINE AND EPIGENOMIC CHANGES (AIM 2), AND INVESTIGATE THE ROLE OF EPIGENETIC CHANGES IN THE PROGRESSION OF AD (AIM 3). A NEW MOUSE MODEL THAT ALLOWS TEMPORAL CONTROL OF EPIGENETIC REPROGRAMMING IN THE FOREBRAIN NEURONS WILL BE USED TO EVALUATE THE THERAPEUTIC EFFECT OF EPIGENETIC REPROGRAMMING IN AD THROUGH A COMBINATION OF MOLECULAR, PHYSIOLOGICAL, BEHAVIORAL, AND HISTOLOGICAL TECHNIQUES. BASED ON OUR PRELIMINARY RESULTS, I HYPOTHESIZE THAT REVERSAL OF TH