Genetics of Fuchs Corneal Dystrophy

福克斯角膜营养不良的遗传学

基本信息

批准号：
10377981
负责人：
John D Gottsch
金额：
$ 39.71万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10377981
关键词：
Affect Age Age-Years Alleles Applications Grants Auditory Threshold Basement membrane Biochemical Biological Assay Biology Blindness CRISPR/Cas technology Caucasians Cell Line Characteristics Clinical Clinical Management Clinical Research Collection Corneal Endothelium Corneal dystrophy Coupled Data Degenerative Disorder Development Disease Disease Progression Endothelium Equilibrium Exons Family Fuchs&apos Endothelial Dystrophy Gene Mutation Gene Proteins Generations Genes Genetic Genetic Load Genetic study Genotype Health Hearing Impairment In Vitro Individual Inherited Investigation Keratoplasty Knock-in Knock-in Mouse Knowledge Laboratories Lesion Link Measures Medical Genetics Membrane Modeling Molecular Mutation National Health and Nutrition Examination Survey Operative Surgical Procedures Pathogenesis Pathogenicity Pathology Pathway interactions Patients Phenotype Physiological Population Prevalence Prognosis Publications Publishing Resources Role Severities System TCF7L2 gene Therapeutic Tissues Transplantation Transplantation Surgery Variant Work causal variant clinical phenotype cohort design experimental study genetic analysis genetic architecture hearing impairment in vivo Model insight loss of function mutation mouse model next generation next generation sequencing novel novel therapeutics progressive hearing loss response socioeconomics solute tool trait transcriptome

项目摘要

Fuchs corneal dystrophy (FCD) is a degenerative disorder of the corneal endothelium that affects nearly 4% of the population above 40 years of age and accounts for the majority of transplants performed each year in the US. Despite the health and socioeconomic impact of the disorder, knowledge of the underlying mechanism and genetic load is sparse, with the only available treatment being corneal transplant surgery. In this grant application, we will extend our previous clinical and genetic studies to a) expand our understanding of the clinical presentation and progression of FCD; and b) begin developing in vitro and in vivo models for the underlying genetic causes of FCD. Our work consists of three specific aims that draw from the strengths of an interdisciplinary team. First, we will expand our patient collection and quantitatively document progression in families linked to known FCD loci (including two novel loci uncovered by our group in the past year). Second, we will take advantage of the knock-in mouse model developed recently in our laboratory to understand the cellular basis of familial loss of function mutations in TCF8 in late-onset FCD families. Finally, taking advantage of our unique cohort, which is enriched for large, multigenerational families, we will identify novel genes for FCD using a combination of traditional genetics tools and exon capture coupled to next generation re- sequencing. These three aims represent a balance of valuable clinical and genetic analyses coupled with functional experiments designed to dissect the molecular components essential to corneal endothelial biology and understand biochemical and cellular mechanisms underlying the disease pathology. Completion of these studies will significantly enhance our understanding of the genetic basis of this common disorder, offer important new insights into its pathomechanism, and provide critical measures for establishing disease presentation and progression rates, which will be necessary for patient management and the design of novel therapeutic paradigms.

福克斯角膜营养不良（FCD）是一种角膜内皮退行性疾病，影响40岁以上人口的近4%，占大多数美国每年都会进行移植手术。尽管对健康和社会经济产生了影响紊乱，对潜在机制和遗传负荷的了解很少，唯一的方法是可用的治疗方法是角膜移植手术。在本次拨款申请中，我们将扩展我们的之前的临床和遗传学研究 a) 扩大我们对临床表现的理解 FCD 的进展； b) 开始开发潜在的体外和体内模型 FCD 的遗传原因。我们的工作包括三个具体目标，这些目标借鉴了一个跨学科的团队。首先，我们将扩大患者收集并定量记录与已知 FCD 位点（包括我们发现的两个新位点）相关的家族的进展去年的小组）。其次，我们将利用开发的敲入小鼠模型最近在我们的实验室了解家族性功能丧失突变的细胞基础晚发 FCD 家族中的 TCF8。最后，利用我们独特的群体，即丰富的大型多代家庭，我们将使用传统遗传学工具和外显子捕获的结合与下一代重新测序。这三个目标代表了有价值的临床和遗传分析的平衡结合旨在剖析必要的分子成分的功能实验角膜内皮生物学并了解其背后的生化和细胞机制疾病病理学。完成这些研究将显着增强我们对这种常见疾病的遗传基础，为其提供重要的新见解病理机制，并为确定疾病表现和提供关键措施进展率，这对于患者管理和新型药物的设计是必要的治疗范式。