INVESTIGATING REGENERATION FACTORS IN THE AGING MAMMALIAN LIVER - PROJECT SUMMARY EVERY HUMAN BEING IS ENDO…

Assistance award details

Assistance award identifier

ASST_NON_K00AG079817_075

FAIN

K00AG079817

Recipient

MASSACHUSETTS INSTITUTE OF TECHNOLOGY

Awarding agency

Department of Health and Human Services

Funding agency

Department of Health and Human Services

Assistance listing (CFDA)

93.866

Total obligated

$186,835

Period

Dec 1, 2023 – May 31, 2029

Fiscal year

2025

Place of performance state

MA

Source file

FY2025_All_Assistance_Full_20261006.zip

Description

INVESTIGATING REGENERATION FACTORS IN THE AGING MAMMALIAN LIVER - PROJECT SUMMARY EVERY HUMAN BEING IS ENDOWED WITH A FINITE NUMBER OF NEURONS THAT MUST ENDURE A LIFETIME OF ENVIRONMENTAL STRESSORS. THIS PROPOSAL FOCUSES ON STUDYING A NEURONAL STRESS RESPONSE AND RECOVERY MECHANISM WITH RELEVANCE TO NEURONAL FUNCTION AND SURVIVAL. THESE STUDIES ARE DIRECTLY APPLICABLE TO HUMAN DISEASE, AGING, AND EXTERNAL IMPACTS OF NEURONAL HEALTH. BRIEFLY, WE HAVE FOUND THAT NEURONAL CELLS RESPOND TO HEAT STRESS IN A NON- CANONICAL WAY, BY DOWNREGULATING TRANSLATION. THIS IS RAPIDLY RECOVERABLE WHEN RETURNED TO BASELINE CONDITIONS WITHIN A FINITE WINDOW, BEYOND WHICH POINT THE CELLS DIE. WE ALSO DISCOVERED THAT STRESS RESPONSE FACTORS WERE BEING ACTIVATED DURING RECOVERY AND ARE IMPORTANT FOR NEURONAL CELL FUNCTION. BASED ON THESE AND OTHER ORIGINAL FINDINGS DURING THE PREDOCTORAL PHASE, OUR CENTRAL HYPOTHESIS IS THAT NEURONS ENDURE HEAT STRESS IN PART THROUGH TRANSLATIONAL REPROGRAMMING TO PREPARE THE SYSTEM FOR SURVIVAL IN THE EVENT THAT RECOVERY IS AN OPTION. TESTING THIS HYPOTHESIS, WE DISCOVERED NEURONS UPREGULATE HSP70 IN ORDER TO SURVIVE THIS RECOVERY PHASE. INTRIGUINGLY, UPREGULATION OF HSP70 HAS BEEN SHOWN TO BE RELEVANT TO A VARIETY OF NEURODEGENERATIVE DISORDERS, INCLUDING ALZHEIMER’S DISEASE. THE RATIONALE FOR THE PROPOSED RESEARCH DURING THE F99 PHASE IS THAT THE MOLECULAR PROGRAMS THAT MEDIATE NEURONAL FUNCTION AND SURVIVAL DURING HEAT STRESS ARE POORLY UNDERSTOOD AND FURTHER UNDERSTANDING WILL PROVIDE CRITICAL INSIGHT INTO THE UNDERLYING CAUSES OF STRESSORS THAT IMPACT THE HUMAN NERVOUS SYSTEM IN HEALTH AND DISEASE. GIVEN THE CRITICAL IMPORTANCE OF NEURONAL STRESS RESPONSE TO HUMAN HEALTH, THE LONG-RANGE OBJECTIVE OF THE PROPOSED RESEARCH IS TO UNDERSTAND THE ROLE OF DYSFUNCTIONAL STRESS RESPONSE IN NEURODEGENERATION AND HOW IT CONTRIBUTES TO DECREASED NEURONAL STRESS RESILIENCE AND INABILITY TO RECOVER FROM STRESS. WE WILL DO THIS THROUGH BIOCHEMICAL, MOLECULAR,