MOLECULAR MECHANISMS OF WERNER SYNDROME HELICASE IN GENOME STABILITY AND AGING - PROJECT SUMMARY PROGEROID…

Assistance award details

Assistance award identifier

ASST_NON_R00AG066938_075

FAIN

R00AG066938

Recipient

THOMAS JEFFERSON UNIVERSITY

Awarding agency

Department of Health and Human Services

Funding agency

Department of Health and Human Services

Assistance listing (CFDA)

93.866

Total obligated

$762,149

Period

Jan 1, 2021 – Jan 31, 2026

Fiscal year

2023

Place of performance state

PA

Source file

FY2023_All_Assistance_Full_20261006.zip

Description

MOLECULAR MECHANISMS OF WERNER SYNDROME HELICASE IN GENOME STABILITY AND AGING - PROJECT SUMMARY PROGEROID SYNDROMES MIMIC AGING AT AN ACCELERATED RATE AND ARE KEY TO UNDERSTANDING BOTH PREMATURE AND NORMAL AGING. ONE CLASS OF PROGEROID SYNDROMES RESULTS FROM DEFECTIVE DNA REPAIR PATHWAYS. FOR EXAMPLE, WERNER SYNDROME (WS)—A RARE INHERITED DISEASE CHARACTERIZED BY PREMATURE AGING AND CANCER—IS CAUSED BY MUTATIONS IN THE DNA REPAIR HELICASE WRN. WS PATIENTS CLOSELY RECAPITULATE MANY NORMAL AGING PHENOTYPES, MAKING WS A MODEL SYSTEM FOR AGING. HOWEVER, THE CELLULAR AND MOLECULAR MECHANISMS INVOLVED IN WS PATHOLOGIES REMAIN POORLY UNDERSTOOD. HERE, I PROPOSE TO ANSWER CRITICAL QUESTIONS REGARDING THE FUNCTIONS OF WRN VIA AN INTERDISCIPLINARY APPROACH THAT INCLUDES STRUCTURAL BIOLOGY, SINGLE-MOLECULE BIOCHEMISTRY, AND CELL BIOLOGY. MY CAREER GOAL IS TO ESTABLISH AN INDEPENDENT RESEARCH PROGRAM DEDICATED TO UNDERSTANDING THE MOLECULAR AND CELLULAR MECHANISMS OF GENOMIC INSTABILITY ASSOCIATED WITH AGING AND AGING-RELATED DISEASES. AS A FIRST STEP TO ACHIEVING THIS GOAL, I HAVE PURSUED POSTDOCTORAL TRAINING IN SINGLE-MOLECULE MICROSCOPY AND BIOCHEMISTRY, COMPLEMENTING MY BACKGROUND IN STRUCTURAL BIOLOGY AND BIOPHYSICAL TECHNIQUES. THE MENTORING PHASE OF THE K99/R00 AWARD WILL PROVIDE ME WITH ADDITIONAL TRAINING IN CRYO-ELECTRON MICROSCOPY, CELL BIOLOGY, TELOMERE BIOLOGY, AND THE BIOLOGY OF HUMAN AGING THROUGH AN EXPERT GROUP OF MENTORS AND ADVISORS. HERE I PROPOSE TO: (1) DETERMINE THE MOLECULAR ARCHITECTURE OF FULL-LENGTH WRN (2) IDENTIFY HOW THE NUCLEASE AND HELICASE ACTIVITIES OF WRN ARE REGULATED (3) DETERMINE HOW WRN COOPERATES WITH TELOMERIC PROTEINS TO UNWIND G-QUADRUPLEXES DURING TELOMERE REPLICATION TO PREVENT TELOMERE LOSS, AND (4) DETERMINE HOW WRN-DEFICIENCY LEADS TO INFLAMMATION AND PREMATURE CELLULAR SENESCENCE. COMPLETION OF THESE AIMS WILL REPRESENT A MAJOR STEP FORWARD IN OUR UNDERSTANDING OF WRN’S ROLE IN PREVENTING GENOMIC INSTABILITY AND WILL LA