IMPACT OF DNA DOUBLE-STRAND BREAKS ON 3D GENOME ORGANIZATION AND GENOME STABILITY IN ALZHEIMER'S DISEASE -…

Assistance award details

Assistance award identifier

ASST_NON_R00AG073466_075

FAIN

R00AG073466

Recipient

BAYLOR COLLEGE OF MEDICINE

Awarding agency

Department of Health and Human Services

Funding agency

Department of Health and Human Services

Assistance listing (CFDA)

93.866

Total obligated

$742,019

Period

Aug 15, 2021 – May 31, 2027

Fiscal year

2024

Place of performance state

TX

Source file

FY2024_All_Assistance_Full_20261006.zip

Description

IMPACT OF DNA DOUBLE-STRAND BREAKS ON 3D GENOME ORGANIZATION AND GENOME STABILITY IN ALZHEIMER'S DISEASE - PROJECT SUMMARY/ABSTRACT THE ACCUMULATION OF DNA DOUBLE-STRAND BREAKS (DSBS) IN NEURONS IS AN EARLY HALLMARK OF ALZHEIMER’S DISEASE (AD). INCREASED DSBS ARE ALSO ASSOCIATED WITH AGING, WHICH IS THE LARGEST RISK FACTOR FOR AD. AD IS ALSO A COMPLEX DISEASE INVOLVING ALL MAJOR BRAIN GLIAL CELL TYPES. THUS, THERE IS A CRITICAL NEED TO UNDERSTAND THE MOLECULAR MECHANISMS OF DSB INDUCED CHANGES IN BOTH NEURONS AND GLIA. THE STRUCTURAL STABILITY OF THE GENOME IS PARAMOUNT IN MAINTAINING A FUNCTIONAL GENOME, AND RECENTLY, THE 3D ORGANIZATION OF THE GENOME HAS EMERGED AS A MAJOR REGULATOR OF GENOME FUNCTION. MY OVERALL HYPOTHESIS IS THAT 3D GENOME REORGANIZATION AND STRUCTURAL GENOME INSTABILITY MEDIATED BY DSBS ARE PRINCIPLE DRIVERS OF AD PATHOGENESIS AND BRAIN AGING. MY OBJECTIVE IS TO DETERMINE HOW AND TO WHAT EXTENT DSBS WITHIN THE NEURONS IMPACT GENOME ORGANIZATION AND THE GLIAL RESPONSE, WITH THE GOAL OF IDENTIFYING MOLECULAR PATHWAYS THAT CAN BE TARGETED AS NOVEL THERAPIES FOR PREVENTING OR HALTING THE PROGRESSION OF NEURODEGENERATION. I WILL USE MOUSE MODELS THAT RECAPITULATE THE PRE-SYMPTOMATIC ACCUMULATION OF DSBS IN NEURONS AND HUMAN IPSC MODELS TO DETERMINE THE DEGREE OF THE 3D GENOME DISRUPTION CAUSED DUE TO DSBS AND THE UNDERLYING MOLECULAR MECHANISMS. I WILL ALSO IDENTIFY THE CONSEQUENCES OF NEURONAL DSBS ON THE STRUCTURAL STABILITY OF THE GENOME BY MEASURING THE FREQUENCY OF DSB MEDIATED CHROMOSOMAL TRANSLOCATIONS IN HUMAN AD NEURONS. INTERESTINGLY, NORMAL NEURONAL ACTIVITY CAUSES DSBS AT IMMEDIATE EARLY GENE PROMOTERS. ALSO, NEURONAL HYPERACTIVITY HAS BEEN REPORTED IN AD. I WILL TEST IF IEGS ARE LOCATIONS OF FREQUENT CHROMOSOMAL TRANSLOCATIONS AFTER NEURONAL HYPERACTIVITY INDUCED IN NEURONAL CULTURE. PREVIOUS STUDIES HAVE SHOWN THAT MICROGLIA TRANSITIONS TO A REACTIVE STATE IN RESPONSE TO NEURODEGENERATION. TO UNDERSTAND THE ROLE OF THE 3D GENOME ORG