The applicant for this K23 Mentored Patient-Oriented Research Career Development Award is a physician scientist with a focus on developing improved care for patients with sickle cell disease (SCD). Chronic kidney disease is present in a large proportion of adults with SCD and is associated with morbidity and early mortality. However, the pathways for sickle nephropathy are unfortunately poorly understood. This proposal will leverage robust genomic strategies to innovatively address mechanistic pathways and susceptibilities for chronic kidney disease in patients with SCD. The underlying hypothesis is that genetic variation existing outside the -globin gene-like cluster is centrally involved in influencing the propensity to develop chronic kidney disease. The applicant will apply exciting preliminary data to develop a candidate gene approach and mechanistic pathways to test this hypothesis via three specific aims. Specific aim #1 will utilize a genomic approach to identify polymorphisms and expression quantitative trait loci (eQTL) in candidate genes to highlight functional pathways for chronic kidney disease in SCD. Specific aim #2 will determine whether the identified gene variants are associated with the progression of chronic kidney disease in a longitudinal cohort to help recognize high-risk SCD patients for kidney disease and guide earlier intervention strategies. Specific aim #3 will investigate mechanisms for understanding how variants in APOL1 and HMOX1 contribute to sickle cell nephropathy. With the guidance of a strong team of mentors, this proposal includes a comprehensive development program incorporating training opportunities through the University of Illinois at Chicago (UIC) School of Public Health, UIC Center for Clinical and Translational Sciences Program, and Department of Medicine. The goals of this proposal are to enhance the applicant's career development and skills in bioinformatic, biostatistical, and translational methods in order to conduct research for understanding the pathobiology of kidney disease in patients with SCD. The applicant is exceptionally positioned to achieving the goals outlined in this proposal through a strong history of productivity and the institutional environment which includes the UIC Comprehensive Sickle Cell Center which cares for over 800 SCD patients and has a long-standing tradition of successful implementation of clinical studies. At the present time, there are only limited therapeutic options available to treat SCD. Developing a better understanding of the susceptibilities and pathways for kidney disease may potentially have a significant impact on this underserved high risk population and will facilitate the long-term goals of the applicant in becoming a successful and independent translational researcher focusing on sickle cell nephropathy.