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Immuno-Metabolic Regulation of Vascular Dysfunction by CD70

Award Number: K08HL177156
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 03/01/2025
PERIOD OF PERFORMANCE END DATE: 02/28/2030

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Immuno-Metabolic Regulation of Vascular Dysfunction by CD70 - PROJECT SUMMARY/ABSTRACT Cardiovascular diseases constitute a tremendous health care burden, and despite increased attention, cardiovascular mortality continues to increase in the United States and worldwide. While immune activation and inflammation are critical to atherosclerotic cardiovascular disease pathogenesis, a significant gap remains in understanding how these pathways cause vascular dysfunction, a central upstream pathophenotype. There is increasing recognition that immune and inflammatory mediators may act by impairing endothelial cell metabolism, causing endothelial injury, and thereby triggering the development of vascular dysfunction. We have recently identified the immune mediator CD70 as a critical regulator of endothelial biology. In this K08 Mentored Clinical Scientist Development Award application, we seek to build on these findings and propose to comprehensively investigate how CD70 regulates key endothelial and metabolic pathways to serve as a potential novel therapeutic for atherosclerotic cardiovascular disease. In addition to this overall scientific goal, the K08 Award Application outlines a detailed career development plan that will enable the principal investigator (PI), Dr. Arvind K. Pandey, to establish himself as an independent physician-scientist in the field of vascular biology and immuno-metabolic regulation of endothelial and vascular function. We have identified that loss of CD70 significantly impairs bioactivity of the key endothelial messenger, nitric oxide (NO), while enhancing cellular and mitochondrial oxidative stress. Our new preliminary data explore a potential mechanism by which CD70 regulates endothelial nitric oxide synthase (eNOS), elucidate how CD70 impairs endothelial metabolism, and demonstrate that CD70 knockdown in mice leads to endothelium-dependent vascular dysfunction. We hypothesize that CD70 regulates vascular dysfunction and inflammation through control of bioactive NO generation and endothelial metabolism. The studies outlined in this proposal will elucidate: 1) CD70 regulation of eNOS through direct protein-protein interaction; 2) mechanisms underlying CD70-induced metabolic and mitochondrial network disruption; and 3) the role of CD70 in exacerbating vascular inflammation and dysfunction in a mouse model of atherosclerosis. Concurrent with these scientific aims, the PI has devised a robust training program to acquire the necessary scientific skillset, training in the responsible conduct of research, and laboratory management skills to transition into an independent investigator with an R01-funded research program by the end of the training period. The PI will receive dedicated mentoring under the direction of his Primary Mentor, Dr. Joseph Loscalzo and Co-Mentor, Dr. Thomas Michel, and the PI’s professional development will be supplemented by his scientific advisory group and focused didactics. The proposed research and training activities will take place at Brigham and Women’s Hospital and Harvard Medical School, which have an excellent environment to support the scientific and training aims. The PI has 75% protected research time and has already been allocated institutional resources to support his research program.


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: 2026 ( Subtotal = $167,400 )
2026	2026	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cardiovascular Diseases Research	000	2	3/5/2026	NON-COMPETING CONTINUATION	$167,400
														Subtotal = $167,400

Issue Date FY: 2025 ( Subtotal = $167,400 )
2025	2025	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cardiovascular Diseases Research	000	1	2/24/2025	NEW	$167,400
														Subtotal = $167,400

Grand Total All Awards = $334,800

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Immuno-Metabolic Regulation of Vascular Dysfunction by CD70

Award Number: K08HL177156

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 03/01/2025

PERIOD OF PERFORMANCE END DATE: 02/28/2030

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