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：
8320257
负责人：
John D Gottsch
金额：
$ 61.76万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-02-01 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8320257
关键词：
15q 18q Affect Age Age of Onset Alleles Animals Applications Grants Award Biological Assay Candidate Disease Gene Cellular biology Chromosomes Chromosomes, Human, Pair 18 Clinical Clinical Data Clinical Protocols Cloning Collagen Collection Cornea Corneal Endothelium Corneal dystrophy Coupled DNA Resequencing Data Degenerative Disorder Descemet&apos s membrane Development Disease Disease Progression Documentation Endothelium Exons Extracellular Matrix Family Foundations Genes Genetic Genetic Load Genetic Materials Genotype Health Healthcare Heterozygote Homeostasis Human Human Genetics In Vitro Introns Investigation Ion Transport Keratoplasty Knock-in Mouse Knowledge Lead Lesion Link Maps Measures Mechanics Microscopic Missense Mutation Modeling Molecular Mus Mutation Natural History Nuclear Operative Surgical Procedures Pathway interactions Patients Penetrance Phenocopy Phenotype Photography Physiological Point Mutation Population Positioning Attribute RNA Interference Recruitment Activity Recurrence Resolution Role Route Screening procedure Therapeutic Time Transcript Untranslated Regions Variant Vascular Endothelial Cell Work base chromosome 5q loss cohort design disease-causing mutation early onset end stage disease genetic pedigree genome wide association study genome-wide improved in vitro Model in vivo in vivo Model insight kindred loss of function loss of function mutation mouse model next generation novel novel therapeutics prognostic socioeconomics tool triple helix

项目摘要

Fuchs corneal dystrophy (FCD) is a degenerative disorder of the corneal endothelium characterized by the formation of guttae, protrusions of the underlying collagen-rich extracellular matrix known as Descemets membrane. The average age of onset is 50, and patients typically reach end stage disease in their 60's and 70's, by which time guttae cover most of the cornea and ion transport functions of the endothelium are severely compromised. FCD is a common condition, with 4% of the population over age 40 affected. 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. This is the first competing renewal of a three year award, in which we will extend our previous clinical and genetic studies to a) expand our understanding of the clinical presentation and progression of FCD; b) identify its underlying genetic causes; and c) begin developing in vitro and in vivo models for FCD mutations. 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, 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 resequencing. Finally, we will extend on our recent discovery of familial loss of function mutations in TCF8 in late-onset FCD families, to generate in vitro and in vivo models of the disorder as a means of understanding its cellular basis. Completion of these studies will enhance significantly the 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 for 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其特征是形成牙胶，底层富含胶原蛋白的突起细胞外基质称为后弹力层。平均发病年龄为50岁，患者通常在 60 多岁和 70 多岁时达到疾病终末期，此时覆盖了大部分角膜，内皮的离子传输功能受到严重影响妥协了。 FCD 是一种常见疾病，4% 的人口年龄超过 40 岁做作的。尽管这种疾病对健康和社会经济产生影响，但对该疾病的了解潜在的机制和遗传负荷很少，唯一可用的治疗方法是角膜移植手术。这是三年期奖项的首次竞争性更新我们将把我们之前的临床和遗传学研究扩展到 a) 扩大我们的了解 FCD 的临床表现和进展； b) 识别其潜在的遗传原因； c) 开始开发 FCD 的体外和体内模型突变。我们的工作包括三个具体目标，这些目标借鉴了跨学科团队。首先，我们将扩大患者收集并定量记录与已知 FCD 基因座（包括两个新基因座）相关的家族的进展我们小组去年发现的）。其次，利用我们独特的群体优势，对于大型多代家庭来说是丰富的，我们将鉴定新的基因 FCD 结合使用传统遗传学工具和外显子捕获以及下一步一代重测序。最后，我们将扩展我们最近发现的家庭损失晚发 FCD 家族中 TCF8 的功能突变，以在体外和体内产生该疾病的模型作为了解其细胞基础的一种手段。完成这些研究将显着增强对这种常见疾病遗传基础的理解疾病，为其病理机制提供重要的新见解，并提供关键的确定疾病表现和进展率的措施，这将是对于患者管理和新型治疗范例的设计是必要的。