Associations of Mitochondrial Genomic Characteristics with Kidney Function and Histopathologic Features

Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. Chronic kidney disease (CKD) is a progressive, age-associated condition that is heterogeneous in both its clinical presentations and histopathological features. While mitochondrial function decline contributes to development of CKD, the implications of mitochondrial genomic characteristics in CKD have not been fully elucidated. Mitochondrial DNA (mtDNA) copy number (-CN) and heteroplasmy (-Het) are emerging indicators of mitochondrial quantity and integrity, respectively, that have been linked to multiple chronic conditions. Importantly, mtDNA-CN and -Het are dynamic measures that may be modifiable. Despite known associations of mitochondrial function with CKD, few studies have examined the relationship between mtDNA-CN or -Het and CKD. Furthermore, mtDNA-CN and -Het have yet to be studied together in relation to kidney tissue-derived histopathological lesions. To address this knowledge gap, we propose the first study to investigate associations of both mtDNA-CN and -Het with CKD and kidney histopathological lesions in large cohort studies. We will leverage existing whole genome sequencing (WGS) and kidney function data from participants in the Trans-Omics for Precision Medicine (TOPMed) program and the Kidney Precision Medicine Project (KPMP). The two programs provide unique resources: TOPMed includes longitudinal kidney function data and readily available mtDNA-CN and -Het previously estimated from WGS in 24,048 participants, while KPMP includes histopathological characterization of kidney biopsies in addition to WGS and kidney function data from 385 participants. Together, the rich resources of TOPMed and KPMP will enable us to test our hypothesis that reduced mtDNA-CN and increased mtDNA-Het are associated with CKD. With data from TOPMed participants, we will test prospective associations of mtDNA-CN and -Het with kidney function decline and incident CKD (Aim 1). With data from KPMP participants, we will assess the relationship of mtDNA-CN and -Het with number and severity of kidney biopsy-derived histopathological lesions (Aim 2). Conducting the proposed research in TOPMed and KPMP will allow us to evaluate associations of mtDNA-CN and -Het with CKD in a large study population, broadening applicability of our findings. In total, study results may shed light on mitochondrial features underlying CKD and guide the development of novel biomarker or therapeutic strategies to treat CKD. Completion of the proposed study aims within a collaborative clinical division under the mentorship of a multi-disciplinary team of experts in multi-omics epidemiology, clinical nephrology research, biostatistics, population health research, mitochondrial genomics, and biomarkers of kidney histopathology will provide the applicant with an excellent foundation for becoming a well-rounded clinician-scientist.