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.

文摘: