ALTERATIONS IN NEURONAL METABOLIC PATHWAYS CONTRIBUTE TO HUMAN COGNITIVE AGING AND ARE EXACERBATED IN ALZHE…
Federal financial assistance recorded from USAspending. This is not a procurement contract.
Assistance award details
- Assistance award identifier
- ASST_NON_R00AG078557_075
- FAIN
- R00AG078557
- Recipient
- UNIVERSITY OF FLORIDA
- Awarding agency
- Department of Health and Human Services
- Funding agency
- Department of Health and Human Services
- Assistance listing (CFDA)
- 93.866
- Total obligated
- $493,018
- Period
- Aug 1, 2023 – Jun 30, 2028
- Fiscal year
- 2025
- Place of performance state
- FL
- Source file
- FY2025_All_Assistance_Full_20261006.zip
Description
ALTERATIONS IN NEURONAL METABOLIC PATHWAYS CONTRIBUTE TO HUMAN COGNITIVE AGING AND ARE EXACERBATED IN ALZHEIMER'S DISEASE - PROJECT SUMMARY TO FIND THERAPIES FOR ALTERING THE COURSE OF AGE-RELATED DISEASES, EXPERIMENTAL METHODS THAT DISCRIMINATE BETWEEN NORMAL AND PATHOLOGICAL AGING PROCESSES ARE NEEDED. NOWHERE IS THIS NEED MORE URGENT THAN IN THE QUEST FOR EFFECTIVE TREATMENTS FOR ALZHEIMERâS DISEASE (AD). DESPITE DECADES OF RESEARCH, AD REMAINS A DEBILITATING, PROGRESSIVE, AND ULTIMATELY FATAL DEMENTIA WITH FEW AND INEFFECTIVE DISEASE-MODIFYING TREATMENT OPTIONS. THE VAST MAJORITY OF CASES (~95%) ARE SPORADIC, WITH NO KNOWN CAUSE ASIDE FROM ADVANCED AGE. AS THE POPULATION OVER AGE 65 GROWS, THE BURDEN OF AD IS DESTINED TO GROW IN LOCKSTEP. AVOIDING THIS FATE REQUIRES RETHINKING WHY EXISTING EFFORTS HAVE BEEN INEFFECTIVE. ALTHOUGH AD IS A DISEASE OF AGED HUMAN BRAINS, MANY AD STUDIES FAIL TO PARSE AGING FROM DISEASE. WE HAVE DEVELOPED A SYSTEM THAT LETS US MODEL ASPECTS OF HUMAN AGE IN VITRO: INDUCED NEURONS (INS). ONCE MATURED, NEURONS OF THE BRAIN NEVER AGAIN REPLICATE THEIR GENOME OR DIVIDE. AS SUCH, POST-MITOTIC NEURONS DOWNREGULATE CELL-CYCLE MEDIATED METABOLIC PATHWAYS USED FOR THE SYNTHESIS OF DNA BUILDING BLOCKS, DEOXYRIBONUCLEOTIDES (DNTS) AND BECOME RELIANT ON THE SALVAGE OF RIBONUCLEOTIDES (RNTS). I ASKED IF THESE FUNDAMENTALLY IMPORTANT HOMEOSTATIC PROCESSES ARE MAINTAINED OVER THE HUMAN LIFESPAN OR IN AD. MULTIPLE EXPERIMENTAL APPROACHES ON INS DERIVED FROM 13 SPORADIC AD (SAD) PATIENTS AGAINST 13 COGNITIVELY NORMAL, AGE-MATCH INDIVIDUALS (CN), REVEALED DRAMATIC DIFFERENCES IN NT POOLS, WITH A SIGNIFICANT INCREASE IN RNTS IN CNS RELATIVE TO YOUNG HEALTHY INS. THIS EFFECT WAS EVEN FURTHER EXACERBATED IN AD INS. I ASK HERE IF THE DRAMATIC INCREASES IN RNTS RESULT IN INCREASED RIBO-SUBSTITUTION IN NUCLEAR AND MITOCHONDRIAL DNA, THUS PROMOTING INCREASED DNA DAMAGE AND BIOENERGETIC DYSFUNCTION IN AGE AND AD. FURTHER, I OBSERVED SIGNIFICANT DIFFERENTIAL E