KO8 Awarded to Dr. Pam Winterberg

Chronic kidney disease (CKD) causes early death from a type of heart failure due to a thick and stiff heart. Our project is trying to better understand what causes the thick and stiff heart during CKD and to find new ways of treating and preventing death from this type of heart failure. Our research focuses on how a particular type of immune cell, called the T cell, is affecting the health of the heart during CKD.

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.