Monday, August 18, 2025 8/18/2025

Mechanisms of Atherogenesis in Clonal Hematopoiesis

Award Number: R00HL157649
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2023
PERIOD OF PERFORMANCE END DATE: 07/31/2026

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Mechanisms of Atherogenesis in Clonal Hematopoiesis - 1 Clonal hematopoiesis (CH), a highly prevalent condition in the elderly, arises from somatic mutations that endow 2 a proliferative advantage to a subset of hematopoietic cells. CH increases the risk of myocardial infarction and stroke 3 independent of traditional risk factors. Relative to other common genetic variants giving rise to CH, the JAK2V617F (JAK2VF) 4 mutation that increases JAK/STAT signaling occurs at a younger age and imparts a substantial risk of premature coronary 5 heart disease (CHD). In CH mutated cells make up only a small fraction of blood cells, however, patients maintain an 6 elevated risk of CHD, suggesting mutant cells may have an outsized impact on their environment. Using murine models of 7 Jak2VF CH we found that IL-1 specifically promotes cell intrinsic proliferation of Jak2VF macrophages, but not wild type 8 (WT) macrophages even within the same atherosclerotic lesions. Administration of antibodies to IL-1 reduced Jak2VF 9 macrophage proliferation and improved features of plaque stability. scRNA-Seq analysis of lesion from mice with Jak2VF 10 expression in all bone marrow cells identified a prominent inflammatory myeloid population that was enriched for genes 11 associated with IL-1 signaling. We found that inflammatory myeloid cell abundance was decreased in the absence of the 12 pyroptosis executioner Gasdermin D (Gsdmd), potentially due to suppressed IL-1 secretion. Therefore, Specific Aim 1 13 will investigate the ability of Jak2VF cells to promote inflammatory phenotypes in WT cells within the same lesion through 14 IL-1 signaling. Mechanistically we have shown that the AIM2 inflammasome is activated in lesions from Jak2VF mice. 15 Deletion of Gsdmd from Jak2VF cells leads to increased DNA double strand breaks in lesions. Bone marrow derived 16 macrophages expressing Jak2VF, but lacking Caspase 1/11 have increased reactive oxygen species, suggesting DNA damage 17 occur upstream of inflammasome activation. Thus, Specific Aim 2 will determine if increased oxidized DNA in Jak2VF 18 macrophages promotes inflammasome activation and inflammation in lesions. Specific Aim 3 will then investigate if 19 truncation mutations in the CH variant protein phosphatase Mg2+/Mn2+ dependent 1D (PPM1D) that leads to inactivation of 20 DNA repair proteins, promotes atherosclerosis. The research proposed here will be accomplished by expanding my 21 conceptual knowledge of DNA damage in macrophages and atherosclerosis and will be complemented by training in single 22 cell sequencing technology to understand how immune cell populations change in lesions based on CH variant status. This 23 training will be supported by rigorous mentoring and collaboration with my scientific advisors during the K99 phase. 24 Together the proposed research and training will elucidate mechanism by which DNA damage and inflammasome activation 25 drive accelerated atherosclerosis in CH which will provide me the knowledge and skills to successfully transition into an 26 independent academic researcher. 27 28 29 30


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 = $248,939 )
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Blood Diseases and Resources Research	000	5	7/24/2025	NON-COMPETING CONTINUATION	$248,939
														Subtotal = $248,939

Issue Date FY: 2024 ( Subtotal = $294,980 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Blood Diseases and Resources Research	001	4	8/9/2024	NON-COMPETING CONTINUATION	$248,981
2024	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Blood Diseases and Resources Research	000	3	2/15/2024	EXTENSION WITH OR WITHOUT FUNDS	$45,999
														Subtotal = $294,980

Issue Date FY: 2023 ( Subtotal = $248,999 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Blood Diseases and Resources Research	001	3	8/26/2023	EXTENSION WITH OR WITHOUT FUNDS	$0
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Blood Diseases and Resources Research	000	3	7/31/2023	EXTENSION WITH OR WITHOUT FUNDS	$248,999
														Subtotal = $248,999

Grand Total All Awards = $792,918

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Mechanisms of Atherogenesis in Clonal Hematopoiesis

Award Number: R00HL157649

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2023

PERIOD OF PERFORMANCE END DATE: 07/31/2026

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