Renal Osteodystrophy Precision Medicine Project

肾性骨营养不良精准医疗项目

基本信息

批准号：
10681662
负责人：
Nicolae Valentin David
金额：
$ 45万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-16 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10681662
关键词：
ATAC-seq Adult Advertisements Advertising Affect Age-Related Osteoporosis American Applications Grants Award Bar Codes Biological Biological Assay Biopsy Biopsy Specimen Blood Bone Diseases Bone Tissue Cardiovascular system Cell Nucleus Cells Cessation of life Chromatin Chromium Chronic Kidney Failure Clinical Clinical Data Clinical Research Communities Complex Consult Data Data Collection Data Files Databases Deformity Deposition Development Dialysis procedure Disease Disease Progression Dry Ice Eligibility Determination Endocrinology Enrollment Ensure Ethanol Ethnic Origin European Event FAIR principles Foundations Fracture Freezing Functional disorder Funding Future Gene Expression Genes Genetic Transcription Genomics Goals Grant Hematology Heterogeneity Histologic Human Hypertension Incidence Individual Infrastructure Institutes International Journals Kentucky Kidney Kidney Diseases Knowledge Knowledge Portal Lead Leadership Letters Libraries Link Manuscripts Measures Metabolic Bone Diseases Methods Minerals Molecular Morbidity - disease rate Musculoskeletal Nature Nephrology Online Systems Osteoporosis Outcome Participant Pathogenesis Pathway Analysis Patients Phenotype Physical Function Population Preparation Prevention Prevention strategy Procedures Process Professional Organizations Protocols documentation Publications Publishing RNA Race Renal Osteodystrophy Research Research Personnel Resources Sampling Science Scientific Advances and Accomplishments Signal Pathway Site Societies Specimen System Time Tissues Translational Research Transplantation Transposase Twitter United States National Institutes of Health Universities Urine Visit Woman Work XCL1 gene base biobank bone bone cell bone loss bone quality career cell type data dissemination data integration data sharing data sharing networks database of Genotypes and Phenotypes design differential expression editorial epigenome epigenomics interest large scale data large-scale database medical specialties meetings men mineralization mortality next generation sequencing novel novel therapeutics outreach program patient oriented phenotypic data portability precision medicine programs recruit response sharing platform skeletal social media statistics therapeutic development tool transcriptome transcriptome sequencing transcriptomics usability virtual web based interface

项目摘要

(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.

（请保持言语，不要PDF）肾骨营养不良（ROD）是一种骨代谢的复杂疾病，几乎影响所有患有慢性肾脏疾病（CKD）的成年人。杆与不良临床结局有关，包括骨质流失，矿化和周转异常，骨骼畸形，断裂，心血管事件和死亡。尽管目前的疗法，与没有CKD的成人相比，成人的骨折发生率高2至100倍。对ROD发病机理的有限了解阻碍了旨在降低CKD患者发病率和死亡率的理论发展。从ROD患者那里获得的基于骨 - 组织的信息，包括改变表观基因组和转录组随疾病进展的函数而缺失，并且高度促进了这种关键的知识差距。我们的长期目标是通过创建基本基础设施来缩小这一知识差距，以促进高影响假说驱动的新型假设驱动的临床和翻译研究，并通过构建大规模数据和组织生物座状的生物定位，将临床，骨骼质量，转录，转录组学和表观综合数据以及储存的尿液，血液和血液样品以及骨骼，骨骼质量，转录组和表观植物数据结合在一起。为此，我们旨在通过简单的转录组（使用3'基因表达）和表观镜头组（使用ATACSEQ）简化骨中单核测序的可变性，并证明骨骼中单核测序的严格和可靠性，以深化我们对基因如何在不同的细胞和棒类型中表达和调节基因的理解。我们的假设是，这个初始和关键的步骤将支持并证明建立由NIH资助的全面开放式NIH资助的数据库，以共享基于骨 - 组织的信息，这些信息从ROD患者那里获得了广泛的科学界。这种资源将为未来的研究努力提供基础，从而导致在有或没有透析的CKD患者中阐明ROD发病机理。这些研究的成功完成是在发现有关未识别的骨骼变化的新信息的过程中的关键里程碑，这些骨骼变化严重。这些目标将由以下操作执行：（1）收集来自12名CKD 3-5D成年人的表型杆的骨活检（n = 4/stage）和4个肾脏健康的成年人，患有与年龄相关的骨质疏松症的参考人群（AIM 1）；（2）确定使用单核RNA和ATAC测序在细胞水平上与骨质疏松症患者的骨转录组和表观基因组的变化（AIM 2）；（3）通过以下方式开发资源的用户管道：1）通过社交媒体，主要的国家和国际社会在广泛的专业中促进资源，并审查了在主要专科期刊上发表的文章和手稿； 2）收集有关数据下载，出版物和赠款应用程序的指标和跟踪信息； 3）开发一个基于Web的交互式访问界面（AIM 3）。这些结果将有助于我们重新定义对Rod发病机理和病理生理学的理解以及针对疾病的预防策略的发展。