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Reverse Engineering of Cell Senescence

Award Number: R01AG073341
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/15/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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Reverse Engineering of Cell Senescence - Abstract Cellular senescence is not just a symptom of aging, but a contributor to aging pathologies. Recent experiments in the mouse show that elimination of senescent cells (a.k.a. senolysis) can reverse several features of the aging process and extend life- and health-span. This has stimulated interest in cell senescence and in finding ways to suppress it that can be easily ported from mouse to human and made even more effective. This implies looking for such drugs as an early senolytic candidate – a kinase inhibitor dasatinib, whose mode of action is unclear. Taking senolytic therapies into human will also require a better understanding of the cell type specific progression towards senescence and diverse sub-types of senescence. In addition to aging per se cells respond to insults such as DNA damage, cell cycle arrest or oncogene activation by expressing aging phenotypes, such as hypertrophy, cell cycle arrest markers, and by secreting growth factors and chemokines, which are thought to produce degenerative responses in nearby cells. Hypertrophy may be one of the most pervasive senescent cell responses but has been hard to study, as until recently we have not had accurate enough means to measure cell mass and cell size, protein and lipid content. Yet, hypertrophy is of special interest because it is deeply connected to cell growth, which is normally under strict control in normal cells. We propose to study how cells, prompted by stressors like radiation or drugs or simply by age, become hypertrophic and how they come to express senescence markers. We have three goals: 1) to trace the progression of cell senescence in molecular terms by quantitative mass spectrometry and phospho-mass spectrometry, and in physiological terms by Raman microscopy, 2) to identify protein circuits responsible for cell senescence, and 3) to find drugs that will prevent, reverse, or eliminate senescent cells. As our tools of perturbation, we have chosen kinase inhibitors. Employing a machine learning approach, we will probe senescent cell development and senescent cell viability via a small set of well-characterized poly-specific kinase inhibitors; then regress a phenotype, such as senescence- specific signaling and senescent cell formation or death, to the activity of key kinases and their downstream circuits. Kinases implicated that way will be independently validated using siRNA knock downs and CRISPR. Additionally, extensive phospho-proteomic profiling will identify the phosphorylation sites on key proteins that most contribute to the phenotypes of senescence and which could be druggable by other means. Taken together, these methods will produce insight into the mode of action of already identified senolytic drugs and suggest new targets and new drugs for seno-therapies. This combination of pharmacology, machine learning, quantitative proteomics and new forms of microscopy can provide fresh insights into aging and suggest potential therapies for aging-related disease.


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 = $646,046 )
2025	2025	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	000	4	12/6/2024	NON-COMPETING CONTINUATION	$593,308
2025	2025	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	001	4	8/11/2025	NON-COMPETING CONTINUATION	$52,738
														Subtotal = $646,046

Issue Date FY: 2024 ( Subtotal = $673,130 )
2024	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	000	3	1/29/2024	NON-COMPETING CONTINUATION	$605,817
2024	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	001	3	5/1/2024	NON-COMPETING CONTINUATION	$67,313
														Subtotal = $673,130

Issue Date FY: 2023 ( Subtotal = $693,878 )
2023	2023	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	000	2	1/19/2023	NON-COMPETING CONTINUATION	$693,878
														Subtotal = $693,878

Issue Date FY: 2022 ( Subtotal = $638,421 )
2022	2022	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	000	1	2/15/2022	NEW	$638,421
														Subtotal = $638,421

Grand Total All Awards = $2,651,475

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Reverse Engineering of Cell Senescence

Award Number: R01AG073341

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/15/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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