Renal Osteodystrophy Precision Medicine Project

肾性骨营养不良精准医疗项目

• 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
• 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

(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.

(请保存在Word中，不要保存为PDF) 肾性骨营养不良(Rod)是一种复杂的骨代谢紊乱，几乎影响所有患有慢性肾脏疾病(CKD)的成年人。Rod与不良的临床结局有关，包括骨丢失、矿化和周转异常、骨骼畸形、骨折、心血管事件和死亡。尽管有目前的治疗方法，但与没有慢性肾脏病的人相比，成人的骨折发生率高出2-100倍。对Rod发病机制的有限认识阻碍了旨在降低CKD患者发病率和死亡率的治疗方法的发展。从ROD患者那里获得的基于骨组织的信息，包括作为疾病进展功能的表观基因组和转录组的改变，是缺失的，并极大地促进了这一关键的知识鸿沟。我们的长期目标是建立一个大规模的数据和组织生物库，整合临床、骨质量、转录和表观基因组数据以及储存的尿液、血液和骨骼样本，通过创建基础设施来促进Rod中高影响力的新型假说驱动的临床和翻译研究，从而缩小这一知识差距。为此，我们的目标是获得可靠和必要的初步数据，评估可变性，并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)来证明骨骼中单核测序的严密性和可靠性，以加深我们对基因如何在不同细胞、Rod类型和肾脏疾病阶段中表达和调控的理解。我们的假设是，这一最初和关键的一步将支持并证明建立一个全面的、开放访问的NIH资助的数据库的合理性，以与广泛的科学界共享从ROD患者那里获得的基于骨组织的信息。这样的资源将为未来的研究努力提供基础，从而阐明接受和不接受透析的CKD患者Rod的发病机制。这些研究的成功完成代表着在发现有关具有严重临床并发症的未被识别的骨变化的新信息的过程中的一个重要里程碑。这些目标将通过：(1)收集12名患有CKD 3-5D(n=4/阶段)的成人CKD 3-5D(n=4/阶段)和4名肾脏健康的老年骨质疏松症参考人群的骨活检标本(目标1)；(2)使用单核RNA和ATAC测序在细胞水平上确定Rod VS骨质疏松症患者骨转录组和表观基因组的变化(目标2)；以及(3)通过以下方式开发资源的用户管道：1)通过社交媒体、主要国家和国际社会在广泛的专科和在主要专业期刊上发表的综述文章和手稿来推广该资源；2)收集有关数据下载、出版物和赠款申请的指标和跟踪信息；3)开发基于网络的交互式开放获取界面(目标3)。这些结果将有助于我们重新定义我们对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。