The Molecular Genetics of Pigmentary Glaucoma

描述(由申请者提供)：本申请的目标是将John Fingert博士培养成一名独立的临床医生和科学家。埃德温·斯通博士和华莱士·阿尔沃德博士将承担起导师的责任，以确保他在基因研究和眼科领域的发展取得成功。这项建议的核心是加强研究遗传性青光眼的遗传学方法的培训。色素弥散综合征(PDS)相关的青光眼因其独特的临床特征而备受关注。PDS很常见(影响高达2.5%的美国人)，由于发病年龄较早，其对个人和社会的影响可能会比许多其他眼病更多地感受到数十年。PDS的显著特征是虹膜色素的释放，导致许多患者发展为色素性青光眼和视力丧失。虽然结构和解剖学因素明显促进了PDS的发展，但流行病学和动物研究已经提供了强有力的证据，证明这种疾病的病理生理学有重要的遗传成分。PDS的遗传基础尚不清楚，然而，爱荷华大学拥有独特的资源来促进PDS致病基因的发现，包括世界级的眼科遗传学研究实验室和大量具有临床特征的PDS患者和家系。这一建议的基本假设是，PDS可能是由虹膜色素产生过程中涉及的基因缺陷引起的。为了验证这一假设，我们将用三种方法搜索PDS疾病基因：首先，我们将使用位置克隆来识别一个大型PDS家系中的致病基因。其次，我们将用遗传标记对大量的PDS患者和对照组进行基因分型，以寻找这些标记的等位基因与PDS之间的关联。第三，我们将对我们的PDS患者队列和对照进行筛查，以确定与色素产生相关的致病基因突变。这些不同的方法将有助于发现引起PDS的基因，并提供对这种疾病的发病机制的洞察，最终目的是促进这种疾病的诊断和治疗的改进。青光眼是一种常见的致盲疾病，有遗传风险因素。一种疾病(色素性青光眼)是由虹膜色素在眼睛内释放引起的。我们正在研究与色素产生有关的基因，作为这种青光眼的原因。

DESCRIPTION (provided by applicant): The goal of this application is to develop Dr. John Fingert into an independent clinician-scientist. Drs. Edwin Stone and Wallace Alward will assume responsibility as mentors to ensure success in his development in the fields of genetic research and ophthalmology. The core of this proposal is intensive training in genetic approaches to studying inherited forms of glaucoma. Glaucoma associated with pigment dispersion syndrome (PDS) is of particular interest for research due to its unique clinical features. PDS is common (affecting up to 2.5% of Americans) and due to the early age of onset, its effects on individuals and society may be felt for decades more than many other eye diseases. The defining characteristic of PDS is the release of pigment from the iris that causes many patients to develop pigmentary glaucoma and vision loss. Although structural and anatomical factors clearly contribute to the development of PDS, epidemiological and animal studies have provided strong evidence for a significant genetic component to the pathophysiology of this condition. The genetic basis of PDS is unknown, however, the University of Iowa has unique resources to facilitate the discovery of PDS-causing genes including a world class ophthalmic genetics research laboratory and a large collection of clinically-characterized PDS patients and pedigrees. The principle hypothesis of this proposal is that PDS may be caused by defects in genes involved in iris pigment production. To test this hypothesis we will search for PDS disease genes with three approaches: First, we will use positional cloning to identify the disease-causing gene in a large PDS pedigree. Second, we will genotype large cohorts of PDS patients and controls with genetic markers in search of an association between alleles of these markers and PDS. Third, we will screen our cohorts of PDS patients and controls for disease-causing mutations in genes associated with pigment production. These diverse approaches will facilitate the discovery of PDS-causing genes and provide insight into the pathogenesis of this disease, with the ultimate goal of facilitating improvements in the diagnosis and treatment of this condition. "Glaucoma is a common, blinding condition with genetic risk factors. One form of disease (pigmentary glaucoma) is caused by release of iris pigment within the eye. We are studying genes involved in pigment production as a cause of this form of glaucoma."