Renal Osteodystrophy Precision Medicine Project

肾性骨营养不良精准医疗项目

• 批准号: 10705266
• 负责人: Nicolae Valentin David
• 金额: $ 44.87万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 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/10705266
• 关键词: ATAC-seq; Abbreviations; 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; International; Journals; Kentucky; Kidney; Kidney Diseases; Knowledge; Knowledge Portal; 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; Postdoctoral Fellow; Preparation; Prevention; Prevention strategy; Procedures; Process; Professional Organizations; Protocols documentation; Publications; Publishing; Race; Renal Osteodystrophy; Research; Research Personnel; Resource Sharing; Resources; Sampling; Science; Scientific Advances and Accomplishments; Signal Pathway; Site; Societies; Specimen; State-of-the-Art Reviews; System; Tissues; Translational Research; Transplantation; Transposase; Twitter; United States National Institutes of Health; Universities; Urine; Visit; Woman; Work; XCL1 gene; biobank; bone; bone cell; bone loss; bone quality; career; cell type; data dissemination; data integration; data sharing; database of Genotypes and Phenotypes; design; differential expression; editorial; epigenome; epigenomics; interest; large scale data; large-scale database; medical specialties; meetings; men; mineralization; mortality; multiple omics; next generation sequencing; novel; novel therapeutics; outreach program; patient oriented; phenotypic data; portability; pre-doctoral; precision medicine; programs; recruit; response; sharing platform; single nucleus RNA-sequencing; skeletal; social media; statistics; therapeutic development; tool; transcriptome; transcriptome sequencing; transcriptomic profiling; transcriptomics; usability; virtual; web based interface

(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.

（请保持文字，不要PDF） 肾性骨营养不良（ROD）是一种复杂的骨代谢疾病，几乎影响所有患有慢性肾脏疾病（CKD）的成年人。ROD与不良临床结局相关，包括骨丢失、矿化和转换异常、骨骼畸形、骨折、心血管事件和死亡。尽管目前的治疗，骨折的发生率是2- 100倍，在成人相比，没有CKD。对ROD发病机制的有限了解阻碍了旨在降低CKD患者发病率和死亡率的治疗方法的开发。从ROD患者中获得的基于骨组织的信息（包括作为疾病进展函数的改变的表观基因组和转录组）缺失，并在很大程度上导致了这一关键的知识缺口。我们的长期目标是通过建立基础设施来缩小这一知识差距，以促进ROD中高影响力的新假设驱动的临床和转化研究，方法是建立一个大规模的数据和组织生物储存库，将临床、骨质量、转录组学和表观基因组学数据沿着储存的尿液、血液和骨骼样本整合在一起。为此，我们的目标是通过同时分析转录组（使用3'基因表达）和表观基因组（使用ATACseq）来获得可靠和必要的初步数据，以评估骨中单核测序的变异性并证明其严谨性和可靠性，从而加深我们对基因如何在不同细胞和ROD类型以及肾病阶段中表达和调节的理解。我们的假设是，这一最初的关键步骤将支持并证明建立一个全面的开放获取NIH资助的数据库，与广大科学界分享从ROD患者获得的基于骨组织的信息。这样的资源将为未来的研究工作提供基础，从而阐明CKD患者的ROD的发病机制，无论是否透析。这些研究的成功完成代表了发现具有严重临床并发症的未识别骨变化的新信息过程中的一个重要里程碑。这些目标将通过以下方式实现：（1）从12名患有CKD 3-5D的成人中收集用于ROD表型分析的骨活检（n=4/分期）和4名患有年龄相关性骨质疏松症的肾脏健康成年人的参考人群（目的1）;（2）使用单核RNA和ATAC测序在细胞水平上确定ROD与骨质疏松症患者的骨转录组和表观基因组的变化（目的2）;和（3）通过以下方式开发资源的用户管道：1）通过社交媒体、跨广泛专业的主要国家和国际协会以及在主要子专业期刊上发表的评论文章和手稿来推广资源; 2）收集关于数据下载、出版物和资助申请的指标和跟踪信息;及3）发展一个互动式开放取用网上界面（目标3）。这些结果将有助于我们努力重新定义我们对ROD发病机制和病理生理学的理解，并制定有针对性的疾病预防策略。