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性眼病的主要原因。在眼睛的前部，它会导致角膜移植排斥、新生血管性青光眼和葡萄膜黑色素瘤等疾病。在后眼中，诸如黄斑变性、糖尿病性视网膜病变和早产儿视网膜病变的病症都由于血管生长和渗漏而破坏视网膜结构。对于许多这些条件有遗传差异，改变了一个人的易感性疾病。我们已经发现近交系小鼠品系之间的血管生成反应性存在显著（> 10倍）差异。我们一直在努力确定导致这种差异的遗传差异。我们已经确定，血管生成反应是由许多不同的“数量性状基因座”（QTL）。在最近的资助期间，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“CEC”的水平与许多近交系小鼠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不仅角膜血管生成反应性与脉络膜新生血管相关，而且这两种特征也由一些相同的基因座控制。最后，对于我们的两个QTL，我们确定了负责血管生成差异的特定分子改变。在这两种情况下，色素控制基因负责角膜血管生成反应的差异。我们现在建议继续这项工作，结合新的可能的单倍型为基础的映射技术与更传统的间隔映射的基础上重组近交系小鼠品系。我们预计，这种组合将使我们能够快速确定负责几个额外的QTL的分子变化。我们希望这将导致识别额外的，意想不到的，血管生成调控途径。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，并为眼部血管生成性疾病提供预后信息的可能性。最后，新的血管生成调控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性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.