ABSTRACT Chronic kidney disease (CKD) confers increased risk for cardiovascular disease. Uremic cardiomyopathy, characterized by left ventricular hypertrophy and diastolic dysfunction is a leading cardiovascular complication of CKD. Targeting traditional CVD risk factors has not significantly improved outcomes in the CKD population, underscoring the need for improved understanding and identification of early risk factors amenable to treatment in the CKD population. Rigorous studies in animal models now support a role for CD4+ T cells in the pathogenesis of heart failure induced by pressure overload and now CKD. This R03 proposal will enhance the activities of the K08-funded PI as they pursue independent funding to further understand the mechanistic role of T cell infiltration in the development of cardiac dysfunction during CKD. The R03 project has two Aims: 1) to determine the role of the CXCR3 pathway in the recruitment of T cells into the heart during CKD, and 2) to determine the functional capacity of heart-infiltrating T cells during CKD. In Aim 1, we will first define the temporal course of chemokine production, including the relative expression and cellular sources of CXCR3 ligands, in relation to T cell infiltration early following CKD-induction. Next, we will determine the necessity of CXCR3 in the early recruitment of T cells during CKD by complementary approaches of pharmacological blockade or knockdown of leukocyte expression of CXCR3. Finally, we will determine whether constitutive expression of CXCR3 by T cells is sufficient for their infiltration into the heart during CKD. In Aim 2, we will define the CD4+ helper T cell subsets infiltrating the heart during CKD in the presence and absence of CXCR3 blockade. Finally, we will determine whether T cell infiltration into the uremic heart is antigen specific by assessing the ability of transgenic T cells that recognize a foreign antigen (ovalbumin, OT-II) to infiltrate the hearts and become activated during CKD. Results from the outlined experiments will provide preliminary data, as well as experience in techniques for the genetic modification of T cells, to support the K08 awardee's application for an R01 proposal to evaluate the impact of T cell trafficking pathways on the development of cardiac dysfunction in CKD.