Genomics of glomerular disease

肾小球疾病的基因组学

• 批准号: 10203943
• 负责人: KRZYSZTOF KIRYLUK
• 金额: $ 87.01万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-14 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10203943
• 关键词: APOL1 gene; Accounting; Address; African American; Autoimmune; Autoimmune Diseases; Biological; Biological Markers; Biopsy; Blood; Clinical; Collaborations; Communities; Coupled; Data; Data Set; Diabetes Mellitus; Diagnosis; Disease; Disease Pathway; End stage renal failure; Etiology; Focal Segmental Glomerulosclerosis; Gene Expression Profile; Gene Expression Regulation; Genetic; Genetic Predisposition to Disease; Genetic Risk; Genetic Translation; Genetic Variation; Genetic study; Genomic medicine; Genomics; Hypertension; IGA Glomerulonephritis; Immune; Inflammatory; Inflammatory Bowel Diseases; Institutes; International; Investments; Kidney Failure; Knowledge; Lupus; Maps; Mediating; Membranous Glomerulonephritis; Meta-Analysis; Molecular; Molecular Disease; Molecular Profiling; Mutation; National Institute of Diabetes and Digestive and Kidney Diseases; Nephrotic Syndrome; Outcome; Participant; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; Patients; Population; Prevention; Prospective Studies; Prospective cohort; Regulator Genes; Renal glomerular disease; Resources; Risk; Role; Sample Size; Sampling; South Asian; Specificity; Steroids; Subcategory; Susceptibility Gene; System; Therapeutic; Translating; United States; Variant; admixture mapping; case control; cell type; clinical translation; cohort; design; disorder subtype; exome; functional genomics; gene function; genetic approach; genetic architecture; genetic association; genetic resource; genetic variant; genome sequencing; genome wide association study; genomic data; genomic locus; insertion/deletion mutation; insight; kidney biopsy; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; peripheral blood; rare variant; risk variant; screening; therapeutic target; transcriptome; transcriptomics; treatment response; validation studies; whole genome

Abstract: Glomerular disorders represent the third-most common cause of end-stage renal disease after diabetes and hypertension. IgA nephropathy (IgAN), focal segmental glomerulosclerosis (FSGS), membranous nephropathy (MN) and minimal change disease (MCD) account for the majority of idiopathic glomerular diseases. Recent genetic studies have identified several genetic loci for these disorders and have begun to identify critical molecular pathways involved in their pathogenesis. However, well-designed and adequately powered genetic association studies are still missing for most glomerular disease types. Moreover, the field is faced with major challenges, including the need to validate the new loci across diverse patient cohorts, understand dysregulated pathways downstream of risk alleles and their consequences on clinical outcomes, define disease-specificity and interactions of risk alleles, and place their functional consequences within a coherent biological network. Such insights can then be translated into clinical benefits, including reliable biomarkers, effective strategies for screening and prevention, and rational selection of potential therapeutic targets. This proposal will address the above challenges by aiming to discover, validate, and fine-map known and novel genetic susceptibility loci by collaborative genetic studies. This will include a pioneering partnership with AstraZeneca and Columbia's Institute for Genomic Medicine to perform whole genome sequencing (WGS) of 4,000 cases of glomerular disease, including the entire CureGN study, the largest prospective cohort of patients with glomerular disorders. This will be followed by international meta-analyses and genetic validation studies in additional 26,000 cases of biopsy-confirmed primary glomerular disorders. Next, we will aim to discover precise pathogenic mechanisms underpinning each of the new genetic loci using systems genetics studies in the CureGN cohort. We will integrate the genetic data with blood transcriptomic studies and clinico-pathologic analyses to identify the key molecular disease drivers and their clinical and histopathologic consequences. Our studies will leverage the largest investment of NIDDK in glomerular diseases to refine the molecular pathogenesis and will be critical in defining targets for novel therapeutic interventions.

抽象的： 肾小球疾病代表糖尿病后终末期肾脏疾病的第三大常见原因 高血压。 IGA肾病（IGAN），局灶性节段性肾小球硬化（FSGS），膜性肾病 （MN）和最小变化疾病（MCD）是大多数特发性肾小球疾病。最近的 遗传研究已经确定了这些疾病的几个遗传基因座，并已开始确定关键 分子途径参与其发病机理。但是，设计良好且功能齐全的遗传 大多数肾小球疾病类型仍然缺少关联研究。而且，该领域面临着专业 挑战，包括需要验证各种患者队列的新基因座的需求，了解失调 风险等位基因下游的途径及其对临床结果的后果，定义疾病特异性 以及风险等位基因的相互作用，并将其功能后果放在连贯的生物网络中。 然后可以将这些见解转化为临床益处，包括可靠的生物标志物，有效的策略 筛查和预防，以及潜在治疗靶标的合理选择。该建议将解决 以上挑战是通过发现，验证和精细地图已知和新颖的遗传敏感性基因座 协作遗传学研究。这将包括与阿斯利康和哥伦比亚的开创性伙伴关系 基因组医学研究所进行4,000例肾小球的整个基因组测序（WGS） 疾病，包括整个治疗研究，是肾小球疾病患者的最大前瞻性队列。 紧随其后的是国际荟萃分析和遗传验证研究 活检确认的原发性肾小球疾病。接下来，我们将旨在发现精确的致病机制 使用CureGN队列中的系统遗传学研究为每个新的遗传基因座支撑。我们将 将遗传数据与血液转录组研究和临床病理分析相结合，以识别关键 分子疾病驱动因素及其临床和组织病理学后果。我们的研究将利用 NIDDK在肾小球疾病中的最大投资以完善分子发病机理，对 定义新的治疗干预措施的靶标。