Comparative Genomics of Glaucoma

描述（由申请人提供）：我们的长期目标是鉴定在某些形式的青光眼发展的早期阶段经历改变的转录调节的基因集合，并在人群中鉴定这些基因中可能使携带它们的个体易患该疾病的大量多态性。青光眼是世界范围内不可逆失明的主要可治疗原因，影响超过6000万人。然而，在人群中易患青光眼的遗传因素在很大程度上仍然是未知的。在此之前，我们建立了黑腹果蝇作为模型系统的研究的影响，人类青光眼相关的“小梁网诱导糖皮质激素反应”蛋白（也称为myocilin; TIGR/MYOC）和确定的转录上调或下调时，TIGR/MYOC是过表达的果蝇眼睛。果蝇仍然是一种无与伦比的多功能遗传模型，它可以用作快速基因发现系统，其中转录谱可以识别当候选青光眼基因在果蝇眼中表达时发生调节改变的基因。在鉴定了这些基因的人类直向同源物后，我们可以问，当通过腺病毒引入TIGR/MYOC（或其他候选青光眼基因）时，它们中的哪一个在灌注的死后人眼中显示出表达的改变。然后，我们将调查是否在候选基因多态性牵连通过这两步筛选与青光眼的发病率在西非人群。（1）评估具有TIGR/MYOC突变体的靶向过表达和靶向RNAi介导的TIGR/MYOC调节基因的下调的果蝇的眼部表型，并进行转基因品系之间的转录改变的分析和比较;（2）评估先前和在特定目标1中发现的果蝇基因的人类同源物，在经受TIGR/MYOC或其它新的候选青光眼基因过表达的灌注死后人眼中上调或下调;并且，在本发明中，（3）评估新的候选青光眼基因的多态性是否与高眼压和青光眼的发病率相关。非洲人群发病率高。这些实验代表了候选疾病易感基因发现的新策略，并将为未来大规模基因组SNP研究奠定基础，以确定可能传递青光眼易感性的完整基因。

DESCRIPTION (provided by applicant): Our long-term goal is to identify ensembles of genes that undergo altered transcriptional regulation during the early stages of the development of some forms of glaucoma, and to identify in the human population at large polymorphisms in such genes that may predispose individuals who harbor them to the development of the disease. Glaucoma is the leading treatable cause of irreversible blindness worldwide and affects more than 60 million people. The genetic factors that predispose to glaucoma in the population at large remain, however, largely unknown. Previously, we established Drosophila melanogaster as a model system for studies of the effects of the human glaucoma-associated "trabecular meshwork inducible glucocorticoid response" protein (also known as myocilin; TIGR/MYOC) and identified transcripts that are up- or down-regulated when TIGR/MYOC is overexpressed in the Drosophila eye. Drosophila remains unsurpassed as a versatile genetic model, which can be used as a rapid gene discovery system, in which transcriptional profiling can identify genes that undergo altered regulation when candidate glaucoma genes are expressed in the Drosophila eye. After identifying human orthologues of such genes we can ask which of them show alterations in their expression in perfused post mortem human eyes when TIGR/MYOC (or other candidate glaucoma genes) are introduced via an adenovirus. We will then investigate whether polymorphisms in candidate genes implicated via this two-step screen are linked to the incidence of glaucoma in a West-African human population. The specific aims of this proposal are to: (l)'Assess the ocular phenotypes of flies with targeted overexpression of TIGR/MYOC mutants and targeted RNAi mediated downregulation of TIGR/MYOC-modulated genes and perform analyses and comparisons of transcriptional alterations among transgenic strains; (2) Assess whether human homologues of Drosophila genes, discovered previously and in Specific Aim 1, are up- or down-regulated in perfused post mortem human eyes subjected to overexpression of TIGR/MYOC, or of other new candidate glaucoma genes; and, (3) Evaluate whether polymorphisms in new candidate glaucoma genes are associated with ocular hypertension and the incidence of glaucoma in a West-African population with high incidence of the disease. These experiments represent a novel strategy for candidate disease susceptibility gene discovery and will lay the foundation for future large scale genomic SNP studies to identify the full complement of genes that may convey susceptibility to glaucoma.