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
基本信息
- 批准号:10622508
- 负责人:
- 金额:$ 65.31万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AccelerationAdipose tissueAffectAnti-Inflammatory AgentsAntidiabetic DrugsApoptoticAreaBiologicalBiological AssayBiologyCandidate Disease GeneCatalogsClinicalCodeComplexComplications of Diabetes MellitusComputerized Medical RecordDataDatabasesDeteriorationDevelopmentDiabetes MellitusDiabetic NephropathyDiseaseDominant-Negative MutationExtracellular Matrix ProteinsFamilyFraser syndromeGenealogyGenesGeneticGenetic studyGoalsHormonesHumanIn VitroIndividualKidneyKidney DiseasesLearningLongitudinal StudiesMusMutationPathway interactionsPatientsPhenotypePilot ProjectsPopulation DatabasePredispositionPropertyProteinsPublishingRecording of previous eventsRenal functionReportingResearchResourcesRiskRoleShapesSusceptibility GeneUniversitiesUtahVariantadiponectinbiobankcandidate identificationcohortconditional knockoutdesigndiabetic patientdrug discoveryepidemiology studyexome sequencinggene discoverygenetic architecturegenetic pedigreegenetic variantgenome wide association studygenome-widehigh riskimprovedin vivoinnovationinsightlink proteinnovelpopulation basedpreventtool
项目摘要
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
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Marcus Guy Pezzolesi其他文献
Marcus Guy Pezzolesi的其他文献
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{{ truncateString('Marcus Guy Pezzolesi', 18)}}的其他基金
Investigating the Genetic Basis of Metabolic Disease and Familial Dysceramidemia in Pacific Islanders
调查太平洋岛民代谢性疾病和家族性神经酰胺血症的遗传基础
- 批准号:
10462627 - 财政年份:2021
- 资助金额:
$ 65.31万 - 项目类别:
Investigating the Genetic Basis of Metabolic Disease and Familial Dysceramidemia in Pacific Islanders
调查太平洋岛民代谢性疾病和家族性神经酰胺血症的遗传基础
- 批准号:
10286704 - 财政年份:2021
- 资助金额:
$ 65.31万 - 项目类别:
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 - 财政年份:2021
- 资助金额:
$ 65.31万 - 项目类别:
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:
10186273 - 财政年份:2021
- 资助金额:
$ 65.31万 - 项目类别:
The role of microRNAs in progressive renal decline in Type 1 diabetes
microRNA 在 1 型糖尿病肾进行性衰退中的作用
- 批准号:
10164613 - 财政年份:2017
- 资助金额:
$ 65.31万 - 项目类别:
Search of Diabetes Nephropathy Genes in Type 1 Diabetes
1 型糖尿病中糖尿病肾病基因的搜索
- 批准号:
8465225 - 财政年份:2011
- 资助金额:
$ 65.31万 - 项目类别:
Search of Diabetes Nephropathy Genes in Type 1 Diabetes
1 型糖尿病中糖尿病肾病基因的搜索
- 批准号:
8189702 - 财政年份:2011
- 资助金额:
$ 65.31万 - 项目类别:
Search of Diabetes Nephropathy Genes in Type 1 Diabetes
1 型糖尿病中糖尿病肾病基因的搜索
- 批准号:
8663891 - 财政年份:2011
- 资助金额:
$ 65.31万 - 项目类别:
Search of Diabetes Nephropathy Genes in Type 1 Diabetes
1 型糖尿病中糖尿病肾病基因的搜索
- 批准号:
8299606 - 财政年份:2011
- 资助金额:
$ 65.31万 - 项目类别:
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