Integrative Omics, Chronic Kidney Disease, and Adverse Outcomes in Older Adults

综合组学、慢性肾病和老年人的不良后果

基本信息

批准号：
10368118
负责人：
JOSEF CORESH
金额：
$ 72.13万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-13 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10368118
关键词：
Address Adult Adverse event Affect Age Albumins Albuminuria Ancillary Study Area Atherosclerosis Risk in Communities Benign Biological Biological Markers Blood Cardiac Cardiovascular Diseases Caring Case-Control Studies Cessation of life Chronic Kidney Failure Clinical Communities Complex CpG dinucleotide Creatinine DNA DNA Methylation Data Disease Disease Outcome Disease Progression Drug Targeting Echocardiography Elderly End stage renal failure Environmental Exposure Epigenetic Process Etiology Event Fibrosis Filtration Functional disorder Funding Funding Mechanisms Gene Expression Genes Genetic Genetic Variation Goals Grant Heart failure Heterogeneity Hospitalization Hour Individual Inflammation Intervention Kidney Letters Longterm Follow-up Measures Mendelian randomization Metabolic Methods Methylation Molecular Multiomic Data National Institute of Diabetes and Digestive and Kidney Diseases Network-based Outcome Participant Pathogenesis Pathway Analysis Pathway interactions Patients Persons Phenotype Physiology Population Prevention Production Prognosis Proteins Proteomics Renal function Research Priority Risk Risk Factors Series Signal Transduction Site Systems Biology Techniques Tissues Urine Variant Visit adjudicate adverse outcome age related aged atherosclerosis risk base clinical risk clinically relevant cohort disease prognosis disorder risk drug development epigenetic variation epigenome-wide association studies epigenomics experience genetic variant genome wide association study heart function high risk high throughput technology improved innovation insight interest metabolomics methylation pattern mortality novel prevent protein metabolite risk prediction therapeutic target therapy development

项目摘要

PROJECT SUMMARY Chronic kidney disease (CKD) affects 500 million people worldwide, with the greatest burden among older adults. People with CKD are at elevated risk for not only end-stage kidney disease, but also cardiovascular disease, heart failure, and death. Existing treatment for CKD is inadequate, and there is vast, poorly understood heterogeneity in disease progression. While genome-wide association studies have identified genetic variants that modulate CKD-associated risk, much of the hereditability of CKD, as well as the molecular basis for how identified variants regulate disease, remains unexplained. Our overarching hypothesis is that an integrated approach combining genetics, epigenetics, proteomics, and metabolomics can yield novel insights into the pathogenesis and prognosis of CKD. Variability in disease may be due in part to variability in DNA methylation, which changes with age and the metabolic milieu and can modify gene expression. Advances in high-throughput technology have revolutionized the breadth and precision of metabolomic and proteomic profiling, enabling unprecedented windows into trans-omic networks. The objective of this study is to use a systems biology approach to integrate genetic sequence variation with DNA methylation patterns, proteomics, and metabolomics in order to advance our understanding and treatment of CKD risk. The proposed grant will pursue biological pathways that affect CKD risk in the ongoing Atherosclerosis Risk Communities (ARIC) study, a contemporary, community-based cohort of white and black adults now aged 70 years and older, with plan for replication in two CKD cohorts and further extension to kidney tissue. The combination of rich phenotyping, comprehensive adjudicated outcomes, and genetic, epigenomic (funded by this grant), proteomic, and metabolomic data provides a unique opportunity to generate insights into the molecular basis of CKD, improve CKD risk prediction, and identify a series of candidate pathways and genes whose products may serve as targets for drug development. With the long-term goal of improving care in patients with CKD, we aim to discover associations between kidney function and metabolites, proteins, and related pathways (Aim 1), identifying specific pathways that provide insight into CKD-associated outcomes, including CKD progression, heart failure, cardiovascular disease, and mortality (Aim 2), and elucidate genetic and epigenetic variation underlying these candidate pathways (Aim 3). The study will use a combination of innovative methods and omics data to identify pathways and genetic variation that are clinical relevant and thus useful in informing the risk prediction and potentially treatment of patients with CKD.

项目概要慢性肾病 (CKD) 影响着全球 5 亿人，其中老年人的负担最大成年人。慢性肾病患者不仅患终末期肾病的风险较高，而且患心血管疾病的风险也较高疾病、心力衰竭和死亡。现有的 CKD 治疗方法不足，而且效果不佳了解疾病进展的异质性。虽然全基因组关联研究已经确定调节 CKD 相关风险的基因变异、CKD 的大部分遗传性以及分子机制已识别的变异如何调节疾病的基础仍不清楚。我们的首要假设是，结合遗传学、表观遗传学、蛋白质组学、代谢组学可以为 CKD 的发病机制和预后提供新的见解。疾病的变异性部分原因可能是DNA甲基化的变异性，它会随着年龄和代谢环境的变化而变化，并且可以修改基因表达。高通量技术的进步彻底改变了检测的广度和范围代谢组学和蛋白质组学分析的精确性，为跨组学网络提供前所未有的窗口。本研究的目的是利用系统生物学方法将基因序列变异与 DNA 甲基化模式、蛋白质组学和代谢组学，以增进我们的理解和 CKD 风险的治疗。拟议的拨款将寻求影响持续动脉粥样硬化中 CKD 风险的生物途径风险社区（ARIC）研究，一项以社区为基础的当代白人和黑人成年人队列研究 70 岁及以上，计划在两个 CKD 队列中进行复制，并进一步扩展到肾组织。这丰富的表型、综合判定结果以及遗传、表观基因组的组合（由这项资助）、蛋白质组学和代谢组学数据提供了一个独特的机会来深入了解 CKD分子基础，提高CKD风险预测，识别一系列候选通路和基因其产品可以作为药物开发的目标。为了改善 CKD 患者的护理，我们的长期目标是发现以下因素之间的关联：肾功能和代谢物、蛋白质和相关途径（目标 1），确定特定途径深入了解 CKD 相关结局，包括 CKD 进展、心力衰竭、心血管疾病疾病和死亡率（目标 2），并阐明这些候选者背后的遗传和表观遗传变异途径（目标 3）。该研究将结合创新方法和组学数据来确定途径和临床相关的遗传变异，因此可用于告知风险预测和潜在的信息 CKD 患者的治疗。