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A Mechanistic and Translational Research Program Linking Impaired Resolution, Defective Efferocytosis, and Clonal Hematopoiesis to the Formation of Clinically Dangerous Atherosclerotic Plaques

Award Number: R35HL145228
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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This R35 proposal represents a comprehensive, long-term program that explores new mechanisms and therapeutic concepts related to the formation of the unique types of atherosclerotic plaques that cause acute cardiovascular disease (CVD). The training and mentoring of young scientists is also a key part of this program. The PI has held multiple NIH grants without interruption for many years, publishes on atherosclerosis and cardiometabolic disease in the highest impact journals, and has a highly successful record of training young scientists to be independent academic researchers. The program will explore new, highly interrelated concepts related to four key areas in which major gaps exist: (i) inflammation resolution and efferocytosis (clearance of dead cells); (ii) pathophysiology of the minority of atherosclerotic lesions that are most clinically important; (iii) amino acid metabolism in M"phi"s as it relates to high-burden efferocytosis; and (iv) aging-related clonal hematopoiesis (CH). Processes that impair inflammation resolution, which are distinct from those that promote inflammation per se, and defective efferocytosis promote the formation of clinically relevant necrotic, thin-capped plaques. The lab's new work indicates that (i) the ability of M"phi"s to internalize multiple apoptotic cells (high-burden efferocytosis) is critical to avoid necrotic plaques (Cell 2017); and (ii) a pathway related to M"phi" metabolism of apoptotic cell-derived amino acids is critical for high-burden efferocytosis. Another exciting new concept supported by preliminary data is that impaired efferocytosis and resolution are exacerbated by CH, which is emerging as a major age-related risk factor for atherosclerotic CVD. The overall vision of the program is to study these new areas by first using (i) mouse and human M"phi"s to elucidate in-depth mechanisms; and (ii) genetically altered mice to test causation in advanced plaque progression. The R35 will also explore the therapeutic potential of these ideas in pre-clinical models, with the hypothesis that resolution mediator therapy will have efficacy and safety advantages over conventional anti-inflammatory therapy. The PI will then use the flexibility and continuity of the R35 program to move into new directions related to human studies. Through a rich network of collaborators at Columbia and elsewhere—including Columbia's Cardiovascular and Metabolic Precision Medicine program— the program will apply the new discoveries to (i) analyses of human atheroma; (ii) human genetics, including subjects with KOs of genes in resolution/efferocytosis pathways through a collaboration with the PROMIS study; and (iii) studies with human monocyte- and iPSC-derived M"phi"s that are amenable to CRISPR/Cas9-mediated genetic engineering, as guided by the program's mechanistic and human genetic data. Through the flexibility and forward-looking nature of the R35 program, the combination of the proposed mechanistic work and human studies will provide a power combination to fill in critical gaps in how dangerous plaque form; to devise novel therapeutic strategies; and to train and mentor young scientists in this critical area of research.


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 = $874,198 )
2024	2024	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Cardiovascular Diseases Research	000	6	2/10/2024	NON-COMPETING CONTINUATION	$874,198
														Subtotal = $874,198

Issue Date FY: 2023 ( Subtotal = $971,337 )
2023	2023	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Cardiovascular Diseases Research	000	5	2/27/2023	NON-COMPETING CONTINUATION	$971,337
														Subtotal = $971,337

Issue Date FY: 2022 ( Subtotal = $971,347 )
2022	2022	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Cardiovascular Diseases Research	000	4	2/7/2022	NON-COMPETING CONTINUATION	$874,212
2022	2022	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Cardiovascular Diseases Research	001	4	6/29/2022	NON-COMPETING CONTINUATION	$97,135
														Subtotal = $971,347

Issue Date FY: 2021 ( Subtotal = $971,355 )
2021	2021	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Cardiovascular Diseases Research	000	3	2/3/2021	NON-COMPETING CONTINUATION	$971,355
														Subtotal = $971,355

Issue Date FY: 2020 ( Subtotal = $979,027 )
2020	2020	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Cardiovascular Diseases Research	000	2	2/21/2020	NON-COMPETING CONTINUATION	$979,027
														Subtotal = $979,027

Issue Date FY: 2019 ( Subtotal = $955,996 )
2019	2019	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Cardiovascular Diseases Research	000	1	3/7/2019	NEW	$955,996
														Subtotal = $955,996

Grand Total All Awards = $5,723,260

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A Mechanistic and Translational Research Program Linking Impaired Resolution, Defective Efferocytosis, and Clonal Hematopoiesis to the Formation of Clinically Dangerous Atherosclerotic Plaques

Award Number: R35HL145228

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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