Role of T cells in Uremic Cardiomyopathy

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Abstract ! The work outlined in this revised proposal for the Mentored Clinical Scientist Research Career Award (K08) will provide the training and mentorship necessary for the candidate to develop into an independent investigator and expert in the immunological consequences of CKD, specifically in relation to cardiovascular comorbidities. Cardiovascular disease is the leading cause of death for the nearly 20 million Americans living with chronic kidney disease (CKD). Uremic cardiomyopathy, characterized by left ventricular hypertrophy (LVH) and diastolic dysfunction, predicts mortality among patients with CKD. The underlying mechanisms contributing to the development of uremic cardiomyopathy are incompletely understood, limiting treatment options. The literature suggests that the accumulation of pro-inflammatory T cells during CKD confer risk for cardiovascular disease via unknown mechanisms, leading us to further explore a role for T cells in uremic cardiomyopathy. We have exciting preliminary data suggesting T cells mechanistically underlie the pathological cardiac changes in an experimental model of CKD. Our overarching hypothesis is that T cells altered by uremia contribute to cardiac remodeling during CKD. The scientific approach in this proposal utilizes a murine model of CKD that results in uremic cardiomyopathy (LVH and diastolic dysfunction) and accumulation of pro-inflammatory T cells. First, we will identify the differential role of the two major subsets of T cells (CD4+ and CD8+) in the pathogenesis of uremic cardiomyopathy. Next, we propose interrogating the role of T cells bearing the co-inhibitory receptors, PD-1 or KLRG1, in uremic cardiomyopathy via adoptive transfer studies and the necessity of the PD-1 signaling pathway using antibody blockade in vivo. Finally, we will investigate the contribution of the co-stimulatory pathway, OX40, including how it relates to the up-regulation of KLRG1 and PD-1 in T cells during CKD. This work will provide important mechanistic insight into the role of T cells during uremic cardiomyopathy, paving the way for novel therapeutic strategies in patients with CKD. We have assembled of a team of NIH-funded mentors with diverse and complementary expertise to support the candidate’s development in three scientific domains: immunology, cardiovascular biology, and chronic kidney disease. The career development plan is structured to expand knowledge in immunology, master advanced experimental methods in immunology, further develop skills in experimental methods in cardiovascular biology, mature skills in scientific communication, and lay a foundation to enable translation of basic science discoveries in the future. The candidate’s primary mentor, Dr. Mandy Ford, is a classically- trained immunologist with expertise in T cell memory development and costimulatory signaling. Dr. Ahsan Husain, as co-mentor, will provide expertise in cardiovascular biology, and Dr. Larry Greenbaum will assist me in forming relationships and project ideas for future translational studies. !