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The role of cGAS in Senesence and the formation of SADS

Award Number: F31AG072748
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/01/2021
PERIOD OF PERFORMANCE END DATE: 11/30/2023

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The role of cGAS in Senesence and the formation of SADS - Project Summary Aging is characterized by a general decline in overall health and a gradual deterioration across multiple organ systems. However, our understanding of the aging process and whether we can improve health span remains a topic of active research. One of the hallmarks of aging is cellular senescence, a stress response that limits the propagation of damaged cells by causing irreversible cell cycle arrest. The DNA damage response is one of the key events leading to senescence. Cells in early senescence show increased satellite transcription and centromere instability and dysmorphism, known as the senescence-associated distension of satellites (SADS). Cyclic GMP-AMP synthase (cGAS) is a cytosolic innate immune sensor that recognizes and responds to microbial and self-DNA. Cytoplasmic cGAS is essential for the establishment of senescence and the secretion of inflammatory mediators characteristic of senescence. However, little is known of cGAS deposition and function in the nucleus. Nuclear cGAS has been reported to inhibit the DNA Damage Response (DDR) via homologous recombination (HR) in the nucleus and to be enriched at repetitive sequences such as centromeres and long interspersed nuclear element (LINE) DNA repeats. Despite these recent findings, the question remains whether cGAS contributes to senescence entry by modulating HR repair and whether cGAS concentration at centromeres and LINEs plays a role in the formation of SADS in early senescence. To answer these questions, I propose the following two aims: Aim 1 will determine whether cGAS inhibition of the DDR contributes to cell entry into senescence. Aim 2 will determine whether cGAS plays a role in SADS formation in senescence. The findings of this project will provide mechanistic insight on the effect of nuclear cGAS in the DDR and centromere stability, and its role in the establishment of senescence. Advancing our knowledge of nuclear cGAS can further current efforts to develop inhibitors of cGAS as potential anti-inflammatory or anti-aging therapy as strategies that extend healthy lifespan. This proposal will be the first to examine the relationship between nuclear cGAS and senescence using cutting edge technology in imaging and unique expertise in its influence at repetitive elements. One of this fellowship's training goals is to develop the repertoire of skills and body of knowledge for a successful career in the biology of aging research. The second goal is to gain experience in effectively communicating research in a variety of settings. To achieve these goals, completion of the proposed research, attending the Gordon Research Conference, presenting at national and international conferences, and my sponsor's mentoring will ensure the success of this training plan. Furthermore, this proposal will take place in the excellent environment of the interdisciplinary and supportive Molecular Biology, Cell Biology, and Biochemistry program at Brown University. Completion of this research and training plan will move the biology of aging field forward and provide me with the ideal preparation towards the career goal of leading an independent academic research laboratory.


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: 2024 ( Subtotal = -$4,976 )
2024	2023	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Aging Research	000	3	9/23/2024	NON-COMPETING CONTINUATION	-$4,976
														Subtotal = -$4,976

Issue Date FY: 2023 ( Subtotal = $17,373 )
2023	2023	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Aging Research	000	3	8/17/2023	NON-COMPETING CONTINUATION	$17,373
														Subtotal = $17,373

Issue Date FY: 2022 ( Subtotal = $46,752 )
2022	2022	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Aging Research	001	2	8/11/2022	NON-COMPETING CONTINUATION	$46,752
2022	2021	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Aging Research	000	1	12/7/2021	NEW	$0
														Subtotal = $46,752

Issue Date FY: 2021 ( Subtotal = $46,036 )
2021	2021	BROWN UNIVERSITY IN PROVIDENCE IN THE STATE OF RHODE ISLAND AND PROVIDENCE PLANTATIONS	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Aging Research	000	1	4/7/2021	NEW	$46,036
2021	2021	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Aging Research	001	1	4/7/2021	NEW	$0
														Subtotal = $46,036

Grand Total All Awards = $105,185

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The role of cGAS in Senesence and the formation of SADS

Award Number: F31AG072748

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/01/2021

PERIOD OF PERFORMANCE END DATE: 11/30/2023

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