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Understanding the mechanistic role of genome stability pathways in regulating cell homeostasis

Award Number: R35GM139610
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/15/2021
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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Understanding the mechanistic role of genome stability pathways in regulating cell homeostasis - PROJECT SUMMARY/ABSTRACT To preserve genomic integrity and maintain homeostasis, cells in our body must effectively respond to both exogenous and endogenous sources of DNA damage. How cellular DNA damage contribute to human disease, including neurological disorders and cancer, is a fundamental area of research. For the past thirteen years, my lab has been focused on studies related to the mechanistic basis of genomic instability. The goal of this MIRA application is to address critical gaps in our understanding of genome stability pathways and how they are differentially utilized in dividing versus non-dividing cells for the proper maintenance of cellular homeostasis. By relaying external information from the cell periphery to the nucleus, cell surface receptor tyrosine kinases (RTKs) respond to growth factors via PI3-kinase (PI3K)-AKT signaling to regulate gene expression and thereby promote growth and/or survival. Similarly, DNA damage threatens genome integrity and upon detection within the nucleus elicits DNA damage response (DDR) signaling to aid in DNA repair and cell cycle checkpoints. For our research program, we will address unique mechanisms related to how key DDR factors contribute to extracellular growth factor signaling crosstalk in dividing and non-dividing cells. To establish these mechanisms, we will utilize an array of innovative experimental approaches including genome-wide sequencing, proximity ligation proteomics, super-resolution microscopy and single-molecule tracking in live cells. We will test the hypothesis that the DDR should be viewed as a broader, stress-responsive network linking nuclear and cytoplasmic effectors to maintain physiological homeostasis through intersecting with growth factor signaling pathways. How this is achieved mechanistically will be a major focus of this application. The second project involves addressing how genotoxic stress in dividing cells impacts DNA replication dynamics and to elucidate novel molecular players that regulate replication fork recovery. Based on our innovative technique called Okazaki fragment sequencing (OK-seq), we are able to directly quantify the efficiency of replication fork initiation and termination at specific sites throughout the genome. Using this technique, we will expand our analysis to understand how genotoxic insults and DNA repair deficiencies contribute to site-specific replication fork-mediated DNA breaks using genome-wide analysis. Deciphering the mechanisms that contribute to replication-associated genomic instability may provide new avenues for targeted cancer treatment.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $423,750 )
2025	2025	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Biomedical Research and Research Training	001	5	1/22/2025	NON-COMPETING CONTINUATION	$381,375
2025	2025	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Biomedical Research and Research Training	002	5	8/5/2025	NON-COMPETING CONTINUATION	$42,375
2025	2024	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Biomedical Research and Research Training	000	4	11/15/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $423,750

Issue Date FY: 2024 ( Subtotal = $423,750 )
2024	2024	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Biomedical Research and Research Training	000	4	2/8/2024	NON-COMPETING CONTINUATION	$381,375
2024	2024	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Biomedical Research and Research Training	001	4	7/23/2024	NON-COMPETING CONTINUATION	$42,375
														Subtotal = $423,750

Issue Date FY: 2023 ( Subtotal = $423,750 )
2023	2023	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Biomedical Research and Research Training	000	3	2/22/2023	NON-COMPETING CONTINUATION	$423,750
														Subtotal = $423,750

Issue Date FY: 2022 ( Subtotal = $423,750 )
2022	2022	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Biomedical Research and Research Training	001	2	7/20/2022	NON-COMPETING CONTINUATION	$42,375
2022	2022	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Biomedical Research and Research Training	000	2	2/16/2022	NON-COMPETING CONTINUATION	$381,375
														Subtotal = $423,750

Issue Date FY: 2021 ( Subtotal = $423,750 )
2021	2021	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Biomedical Research and Research Training	000	1	4/15/2021	NEW	$423,750
														Subtotal = $423,750

Grand Total All Awards = $2,118,750

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Understanding the mechanistic role of genome stability pathways in regulating cell homeostasis

Award Number: R35GM139610

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/15/2021

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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