TARGETING H4K20 METHYLATION TO REJUVENATE AGED STEM CELL EPIGENOME AND REGENERATIVE FUNCTION. - ABSTRACT AS…

Assistance award details

Assistance award identifier

ASST_NON_R00AG071736_075

FAIN

R00AG071736

Recipient

UNIVERSITY OF WISCONSIN SYSTEM

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

Jun 15, 2022 – Aug 31, 2027

Fiscal year

2024

Place of performance state

WI

Source file

FY2024_All_Assistance_Full_20261006.zip

Description

TARGETING H4K20 METHYLATION TO REJUVENATE AGED STEM CELL EPIGENOME AND REGENERATIVE FUNCTION. - ABSTRACT AS WE AGE, THE INTRINSIC ABILITY OF STEM CELLS TO SELF-RENEW AND DIFFERENTIATE TO MAINTAIN TISSUE INTEGRITY DRAMATICALLY DECLINES. THEREFORE, UNDERSTANDING THE PROCESSES LEADING TO STEM CELL DYSFUNCTION WITH AGE IS ESSENTIAL FOR THE FUTURE DEVELOPMENT OF NOVEL, EFFECTIVE STEM CELL-BASED THERAPIES TO TREAT DISORDERS ASSOCIATED WITH AGING. THEREFORE, MY LONG-TERM GOAL IS TO ELUCIDATE THE EPIGENETIC MECHANISMS OF STEM CELL AGING, MANIPULATE THEM TO REJUVENATE AGED TISSUE, AND PROMOTE HEALTHY AGING. MORE SPECIFICALLY, THE INSIGHT PROVIDED BY THIS PROPOSAL WOULD BE USED TO DEVISE STRATEGIES TO REJUVENATE MUSCLE AND HEMATOPOIETIC STEM CELL FUNCTION, AND THEREFORE PROMOTE SKELETAL MUSCLE RECOVERY AND REDUCE AGE-ASSOCIATED SYSTEMIC LOW- GRADE CHRONIC INFLAMMATION. TO ACCOMPLISH THIS OBJECTIVE, WE WILL UTILIZE MOUSE GENETIC MODELS, MODELS OF SKELETAL MUSCLE DEGENERATIVE INJURY AND MODERATE EXERCISE (VOLUNTARY WHEEL RUNNING; VWR), CELL CULTURE SYSTEMS, IMAGING ANALYSIS, SMALL MOLECULE INHIBITORS, FLOW CYTOMETRY ANALYSIS, PHYSIOLOGICAL MEASURES OF RECOVERY, GENOMICS, AND EPIGENOMICS (CLEAVAGE UNDER TARGETS AND TAGMENTATION; CUT&TAG). IN AGED MICE, BOTH MUSCLE STEM CELL (MUSC) AND HEMATOPOIETIC STEM AND PROGENITOR CELL (HSPC) QUIESCENCE IS DISRUPTED, LEADING TO REDUCED REGENERATIVE CAPACITY. RECENT STUDIES USED VWR TO RESTORE QUIESCENCE AND REJUVENATE BOTH MUSC AND HSPC FUNCTION IN AGED MICE. THE EPIGENETIC LANDSCAPE IN BOTH STEM CELL POPULATIONS CHANGES DRAMATICALLY, YET THE MECHANISMS UNDERLYING THESE EVENTS AS WELL AS THEIR CONTRIBUTION TO AGE-ASSOCIATED DYSFUNCTION REMAIN UNDERSTUDIED. THE LYSINE METHYLTRANSFERASE 5A (KMT5A) IS THE SOLE ENZYME CATALYZING MONOMETHYLATION OF LYSINE 20 ON HISTONE H4 (H4K20ME1), WHICH IS REQUIRED FOR SUBSEQUENT DI- AND TRI-METHYLATION BY KMT5B AND KMT5C, RESPECTIVELY. METHYLATION OF H4K20 IS CRITICAL FOR CHROMATIN ORGANIZATION AND REGULATION