Renal Osteodystrophy Precision Medicine Project

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(PLEASE KEEP IN WORD, DO NOT PDF) Renal osteodystrophy (ROD) is a complex disorder of bone metabolism that affects virtually all adults with chronic kidney disease (CKD). ROD is associated with adverse clinical outcomes including bone loss, mineralization and turnover abnormalities, skeletal deformities, fractures, cardiovascular events and death. Despite current therapies, fracture incidence is 2- to 100-fold higher in adults with compared to those without CKD. Limited knowledge of ROD pathogenesis impedes development of therapeutics aimed at reducing morbidity and mortality of CKD patients. Bone-tissue based information obtained from patients with ROD that includes altered epigenome and transcriptome as a function of disease progression is missing and highly contributes to this critical knowledge gap. Our long-term goal is to close this knowledge gap by creating the fundamental infrastructure to facilitate high-impact novel hypothesis-driven clinical and translational research in ROD by building a large-scale data and tissue biorepository integrating clinical, bone quality, transcriptomic and epigenomic data along with stored urine, blood and bone samples. To this effect, we aim to obtain robust and necessary preliminary data assessing the variability and demonstrating the rigor and reliability of single nuclei sequencing in bone by simultaneous profiling of the transcriptome (using 3’ gene expression) and epigenome (using ATACseq) to deepen our understanding of how genes are expressed and regulated across different cells and ROD types and kidney disease stages. Our hypothesis is that this initial and critical step will support and justify the establishment of a comprehensive open-access NIH-funded database to share bone-tissue based information obtained from patients with ROD with the broad scientific community. Such a resource will provide the underpinnings for future research endeavors leading to the elucidation of the pathogenesis of ROD in CKD patients with and without dialysis. Successful completion of these studies represents a crucial milestone in the process of discovering new information regarding unrecognized bone changes that have severe clinical complications. These goals will be executed by: (1) Collecting bone biopsies for phenotyping ROD from 12 adults with CKD 3-5D (n=4/stage) and a reference population of 4 kidney-healthy adults with age-related osteoporosis (Aim 1); (2) Determining changes in osseous transcriptome and epigenome of patients with ROD vs osteoporosis at the cellular level using single nuclei RNA and ATAC sequencing (Aim 2); and (3) Developing a user pipeline for the resource by: 1) promoting the resource via social media, major national and international societies across a broad spectrum of specialties and review articles and manuscripts published in major subspecialty journals; 2) collecting metrics and tracking information on data downloads, publications and grant applications; and 3) developing an interactive open access web-based interface (Aim 3). These results will contribute to our efforts to redefine our understanding of ROD pathogenesis and pathophysiology and the development of disease targeted prevention strategies.