Identifying a Disease Gene Causing Primary Open Angle Glaucoma

描述（由申请人提供）： 在美国，原发性开角型青光眼（POAG）是普通人群的第二大致盲原因，也是非裔美国人的主要致盲原因。由于该病即使在相当晚期也无症状，许多患者直到发生不可逆性失明才被诊断为POAG。关于POAG的基本致病机制的基本问题仍然没有答案。改善青光眼患者的治疗需要更好地了解疾病机制和早期检测策略的发展。我们广泛的长期目标是了解疾病的病理生理学，并提供早期发现和更好地治疗这种毁灭性疾病的工具。POAG家族史是最重要的危险因素之一，这一事实表明POAG的遗传成分。鉴定导致POAG的基因对于开发POAG的改进治疗和早期诊断策略至关重要。40多年前，建立了一个遗传性POAG的比格犬群体，至今仍然是人类POAG的唯一自然发生的动物模型。利用这个成熟的模型，我们最近确定了一个小的遗传间隔，其中包含导致比格犬POAG的基因突变。本项目的目的是确定导致比格犬POAG的基因突变。为了实现这一目标，我们将应用新一代测序技术来确定整个区域的DNA序列。将通过比较POAG比格犬群中受影响和未受影响犬以及无关未受影响比格犬的序列，鉴定候选遗传变异体。这些遗传变异将确定候选疾病基因。将通过研究候选基因在受累和未受累比格犬眼组织中的表达来检测候选基因的有效性。本文的工作将促进和推广序列捕获和新一代测序技术在疾病基因鉴定中的应用。该项目的成功完成将导致识别和验证导致POAG的基因，这将可能是对青光眼研究的重大贡献，从而改善青光眼患者的治疗和早期检测。 公共卫生相关性： 叙述本提案的主要目的是确定基因引起原发性开角型青光眼的比格犬。基于我们的初步结果，我们计划该基因将是新的，并参与房水流出调节。

DESCRIPTION (provided by applicant): Project Summary/Abstract In the United States, Primary Open Angle Glaucoma (POAG) is the second leading cause of blindness in the general population and the leading cause of blindness among African Americans. Due to the asymptomatic nature of the disease even at considerably advanced stages, many patients are not diagnosed with POAG until irreversible blindness has occurred. Fundamental questions about basic pathogenic mechanisms of POAG remain unanswered. Improved treatment for glaucoma patients requires better understanding of the disease mechanisms and development of early detection strategies. Our broad long term goals are to understand the disease pathophysiology and to provide tools for early detection and better treatment of this devastating disease. A genetic component for POAG is suggested by the fact that family history of the disease is one of the most important risk factors. Identification of genes contributing to POAG is of primary importance to develop improved treatment and early diagnosis strategies for POAG. Over 4 decades ago, a colony of Beagles with hereditary POAG was established, and to this day remains the only naturally occurring animal model for human POAG. Taking advantage of this well-established model, we have recently identified a small genetic interval that contains the genetic mutation causing POAG in the Beagles. The objective of this project is to identify the genetic mutation causing POAG in Beagles. To accomplish this goal, we will apply the emergent technology of Next Generation Sequencing to determine the DNA sequence of the entire region. Candidate genetic variants will be identified by comparing the sequences of affected and unaffected dogs from the POAG Beagle colony and unrelated unaffected Beagles. These genetic variants will identify candidate disease genes. Validity of the candidate genes will be tested by investigating their expression in ocular tissues from affected and unaffected Beagles. The work proposed here would promote and extend the use of the new genetic technologies of sequence capture and Next Generation Sequencing in the application of disease gene identification. Successful completion of this project would result in identification and verification of a gene causing POAG, which will likely be a major contribution to glaucoma research leading to improved treatment and early detection for glaucoma patients. PUBLIC HEALTH RELEVANCE: Narrative The main objective of this proposal is to identify the gene causing primary open angle glaucoma in Beagles. Based on our preliminary results, we project that the gene will be novel and involved in aqueous humor outflow regulation.