Identifying a Disease Gene Causing Primary Open Angle Glaucoma

描述(由申请人提供)： 项目摘要/摘要在美国，原发性开角型青光眼(POAG)是普通人群中第二大致盲原因，也是非裔美国人致盲的主要原因。由于这种疾病的无症状性质，即使在相当严重的阶段，许多患者直到发生不可逆转的失明才被诊断为POAG。关于POAG基本发病机制的基本问题仍未得到解答。改进青光眼患者的治疗需要更好地了解疾病机制并制定早期检测策略。我们广泛的长期目标是了解这种疾病的病理生理学，并为这种毁灭性疾病的早期发现和更好的治疗提供工具。家族病史是POAG最重要的危险因素之一，这一事实提示POAG的遗传因素。识别与POAG相关的基因对于改进POAG的治疗和早期诊断策略具有重要意义。40多年前，一群患有遗传性POAG的比格犬被建立起来，直到今天，它仍然是唯一的自然发生的人类POAG动物模型。利用这一成熟的模型，我们最近发现了一个小的遗传区间，其中包含导致比格犬POAG的基因突变。该项目的目标是确定引起比格犬POAG的基因突变。为了实现这一目标，我们将应用下一代测序的新兴技术来确定整个区域的DNA序列。候选遗传变异将通过比较POAG Beagle群体中受影响和未受影响的狗以及不相关的未受影响的Beagle的序列来确定。这些基因变异将识别候选的疾病基因。候选基因的有效性将通过研究它们在受影响和未受影响的比格犬眼组织中的表达来测试。这项工作将促进和推广序列捕获和下一代测序等新的基因技术在疾病基因识别中的应用。该项目的成功完成将导致识别和验证导致POAG的基因，这可能会对青光眼研究做出重大贡献，从而改进青光眼患者的治疗和早期发现。 公共卫生相关性： 叙述这项建议的主要目的是确定导致比格犬原发性开角型青光眼的基因。根据我们的初步结果，我们推测该基因将是一个新的基因，并参与房水流出的调节。

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.