PROJECT SUMMARY/ABSTRACT Diabetic kidney disease (DKD) is clinically and mechanistically heterogeneous. Individual patients present with variable trajectories of estimated glomerular filtration rate (eGFR) and albuminuria that may not be concordant with severity of kidney histopathological injury, reflective of long-term outcomes, or predictive of response to therapy. Elucidating the molecular mechanisms underlying DKD pathogenesis may help explain differences in DKD’s clinical presentation and allow implementation of novel personalized diagnostic, prognostic, and therapeutic strategies. Autophagy, the process by which cytoplasmic components such as damaged organelles are delivered to lysosomes and degraded, is essential for maintenance of cellular homeostasis in the kidney and is a promising mechanism to evaluate in DKD. While kidney autophagy has been studied in extensively in experimental diabetes models, the role of autophagy in human DKD remains a major knowledge gap. The overall goal of the project proposed here is to comprehensively characterize autophagy in human DKD using clinical, histopathological, and molecular phenotyping, establishing a foundation for mechanistically- targeted diagnostic and therapeutic strategies. This project will leverage kidney molecular, clinical, and histopathologic data from the Kidney Precision Medicine Project (KPMP), a longitudinal type 2 diabetes Pima Indian cohort, and a University of Washington (UW) kidney biopsy cohort. In Aim 1, I will define clinical, molecular, and histopathological patterns of autophagy in DKD in the KPMP. Specifically, I will compare markers of autophagy in kidney tissue (autophagosome number assessed via electron microscopy, autophagy- related gene expression, autophagy-related protein concentrations) between adults with DKD and controls. I will also investigate associations of kidney autophagy markers with clinical and histopathological features. In Aim 2, I will test associations of kidney autophagy markers with long-term changes in measured GFR and albuminuria in the Pima Indian cohort. In Aim 3, I will develop urine and blood biomarker signatures, developed and internally validated in the KPMP and externally validated in the Pima Indian and UW cohorts. I aim to establish a career as a physician-scientist with a research focus on DKD and precision medicine. To accomplish my research and career development goals, I have designed a training plan supported by a team of mentors and collaborators with expertise in DKD, bioinformatics, epidemiology, and kidney histopathology. This project will generate novel insights into autophagy in DKD and urine and blood biomarker signatures for assessing kidney tissue autophagy which can be applied to other cohorts. Improved understanding of autophagy in DKD may pave the way for molecular-based subgroups with distinct prognoses and responses to existing and novel therapies.