Genetic and Functional Analysis of Rapid Renal Decline in Diabetes: A Family-based Approach to Accelerate Gene Discovery

糖尿病肾病快速衰退的遗传和功能分析：加速基因发现的基于家族的方法

• 批准号: 10392503
• 负责人: Marcus Guy Pezzolesi
• 金额: $ 65.38万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10392503
• 关键词: Adipose tissue; Affect; Anti-Inflammatory Agents; Antidiabetic Drugs; Apoptotic; Area; Biological; Biological Assay; Biology; Candidate Disease Gene; Catalogs; Clinical; Code; Complex; Complications of Diabetes Mellitus; Computerized Medical Record; Data; Databases; Development; Diabetes Mellitus; Diabetic Nephropathy; Disease; Dominant-Negative Mutation; Extracellular Matrix Proteins; Family; Fraser syndrome; Genealogy; Genes; Genetic; Goals; Hormones; Human; In Vitro; Individual; Kidney; Kidney Diseases; Longitudinal Studies; Mus; Mutation; Pathway interactions; Patients; Phenotype; Pilot Projects; Population Database; Predisposition; Property; Proteins; Publishing; Recording of previous events; Renal function; Reporting; Research; Resources; Risk; Role; Shapes; Susceptibility Gene; Universities; Utah; Variant; adiponectin; base; biobank; cohort; conditional knockout; design; diabetic patient; drug discovery; exome sequencing; gene discovery; genetic architecture; genetic epidemiology; genetic pedigree; genetic variant; genome wide association study; genome-wide; high risk; improved; in vivo; innovation; insight; link protein; novel; population based; prevent; tool

PROJECT SUMMARY Diabetic nephropathy (DN) is a complex, heterogeneous complication of diabetes that is characterized by progressive renal decline. While genetic factors are known to contribute to DN susceptibility, despite intense effort, the identification of variants that underlie its risk has been challenging, largely due to the scarcity of well- characterized cohorts designed to investigate the genetic basis of rapid renal decline. To overcome this bottleneck, we’ve developed an innovative family-based approach to accelerate gene discovery in DN that integrates unparalleled resources, including the Utah Diabetes Database (UDDb), which contains electronic medical record data for more than 350,000 diabetic patients, the Utah Population Database, a unique population-based genealogy resource containing family histories and demographic data for 14 million individuals, and the Intermountain Biorepository, a large biorepository containing biospecimens for 147,000 patients in the UDDb. Using these resources, we’ve established one of the world’s largest and well- characterized cohorts of diabetic patients with rapid progression of renal decline and identified >450 large, multigenerational pedigrees enriched for this key feature of DN. As part of a recent pilot study applying our approach, we identified putative disease-causing variants in 2 genes (ADIPOQ and FRAS1) not previously known to contribute to DN. These strong preliminary findings highlight the power of family-based genetics to discover novel genes that contribute to rapid renal decline and DN. We believe that these studies are just the ‘tip of the iceberg’ and that additional predisposing genes and pathways remain to be discovered. To further advance this research, we will 1) define the pathophysiological mechanisms through which ADIPOQ and FRAS1 affect rapid progression of renal decline in DN families by i) examining the role of ADIPOQ mutation on renal decline and DN development using genetically edited mice (mice carrying the human mutation identified in a high-risk pedigree have already been generated) and ii) examining the role of FRAS1 mutation on renal decline and DN development using genetically edited mice. 2) Establish a comprehensive catalog of coding variation in DN families enriched for rapid progression of renal decline by i) prioritizing high-risk pedigrees enriched for rapid renal decline using innovative tools developed at the University of Utah and identifying select individuals from these families to optimize WES-based gene discovery and ii) performing WES-based gene discovery in newly identified high-risk pedigrees enriched for rapid renal decline. 3) Evaluate the causal relationship between genetic variants identified in DN families enriched for rapid progression of renal decline and rapid renal decline by i) prioritizing candidate genes discovered using WES to identify the most promising candidates using statistical and biological evidence and ii) performing in vitro and in vivo assays to investigate the biological impact of prioritized candidate genes. Combined, the proposed research will significantly advance our understanding of the genetics and biology of DN and rapid renal decline.

项目总结