Identification of Common Polymorphisms Affecting Angiogenesis

描述（由申请人提供）：不适当的血管生成是西方世界致盲眼病的主要原因。在眼睛的前部，它会导致角膜移植排斥反应、新生血管性青光眼和葡萄膜黑色素瘤。在后眼，黄斑变性、糖尿病视网膜病变和早产儿视网膜病变等疾病都因血管生长和渗漏而破坏视网膜结构。对于许多这些疾病来说，遗传差异会改变个体对疾病的易感性。我们发现，在近亲繁殖的小鼠品系中，血管生成反应性有显著差异（bbb10倍）。我们一直在努力找出造成这种差异的基因差异。我们已经确定血管生成反应性是由许多不同的“数量性状位点”（qtl）控制的。在最近的资助期内，我们已经证明了两个额外的特征与血管生成反应性相关。首先，我们确定了循环“EPCs”和“CECs”的水平与许多近交小鼠品系的血管生成反应密切相关。然后，我们使用激光诱导的脉络膜新生血管模型来证明角膜血管生成反应性不仅与脉络膜新生血管相关，而且这两种特征也由一些相同的位点控制。最后，对于我们的两个qtl，我们确定了导致血管生成差异的特定分子改变。在这两种情况下，色素控制基因对角膜血管生成反应的差异负责。我们现在建议通过将一种新的基于单倍型的定位技术与基于重组近交小鼠品系的更传统的间隔定位技术相结合来继续这项工作。我们预计这种组合将使我们能够快速识别导致其他几个qtl的分子改变。我们期望这将导致额外的，意想不到的，血管生成调节途径的识别。作为研究设计的结果，这些途径也可能在人类中表现出多态性。这些研究将为人类研究提供候选基因，并可能为眼部血管生成疾病提供预后信息。最后，新的血管生成调节途径的鉴定有可能支持新的血管生成调节疗法的发展。因此，这些研究可能会改善致盲眼病的预后和治疗方法。

DESCRIPTION (provided by applicant): Inappropriate angiogenesis is the leading cause of blinding eye disease in the western world. In the anterior portion of the eye it contributes to such conditions as corneal graft rejection, neovascular glaucoma, and uveal melanoma. In the posterior eye, conditions such as macular degeneration, diabetic retinopathy, and retinopathy of prematurity all disrupt retinal structure as a result of vessel growth and leakage. For many of these conditions there are genetic differences which alter an individual's susceptibility to disease. We have discovered a significant (> 10-fold) difference in angiogenic responsiveness among inbred mouse strains. We have been working to identify the genetic differences responsible for this difference. We have determined that angiogenic responsiveness is controlled by many different "quantitative trait loci" (QTLs). In the most recent funding period, we have demonstrated that two additional traits correlate with angiogenic responsiveness. First, we determined that the levels of circulating "EPCs" and "CECs" are closely correlated with angiogenic responsiveness in a number of inbred mouse strains. Then we used a laser-induced model of choroidal neovascularization to demonstrate that not only was corneal angiogenic responsiveness correlated with choroidal neovascularization, but both traits are also controlled by some of the same loci. Finally, for two of our QTLs we identified the specific molecular alteration responsible for the difference in angiogenesis. In each of these two cases a pigment-controlling gene was responsible for the difference in corneal angiogenic responsiveness. We now propose to continue this work by combining a newly possible haplotype-based mapping technique with more traditional interval mapping based on recombinant inbred mouse strains. We anticipate that this combination will allow us to rapidly identify the molecular alterations responsible for several additional QTLs. We expect that this will result in the identification of additional, unexpected, angiogenesis regulatory pathways. As a result of the study design, these pathways are also likely to also exhibit polymorphism in humans. These studies will provide candidate genes for human studies and the possibility of providing prognostic information for ocular angiogenic diseases. Finally, the identification of novel angiogenesis regulatory pathways has the potential to support the development of novel angiogenesis modulatory therapeutics. As a result, these studies may improve both prognostic and therapeutic approaches to blinding eye disease.