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.