Identification of Common Polymorphisms Affecting Angiogenesis

描述(申请人提供)：不适当的血管生成是西方世界失明眼病的主要原因。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等情况。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情况都会由于血管生长和渗漏而破坏视网膜结构。对于这些疾病中的许多情况，都存在基因差异，这些差异会改变个人对疾病的易感性。我们发现近交系小鼠的血管生成反应性有显著差异(10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受许多不同的“数量性状基因座”(QTL)控制。在最近的资助期，我们已经证明了另外两个特征与血管生成反应相关。首先，我们确定了在一些近交系小鼠中，循环中的“内皮祖细胞”和“内皮祖细胞”水平与血管生成反应密切相关。然后，我们使用了一个激光诱导的脉络膜新生血管模型来证明，角膜新生血管反应性不仅与脉络膜新生血管相关，而且这两个特征也受一些相同的基因座控制。最后，对于我们的两个QTL，我们确定了导致血管生成差异的特定分子改变。在这两个病例中，一个色素控制基因导致了角膜新生血管反应性的差异。我们现在建议继续这项工作，将一种新的可能的基于单倍型的作图技术与更传统的基于重组近交系小鼠品系的区间作图相结合。我们预计，这一组合将使我们能够快速确定导致几个额外QTL的分子变化。我们预计，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，这些通路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，并可能为眼部血管新生疾病提供预后信息。最后，识别新的血管生成调节通路有可能支持新的血管生成调节疗法的开发。因此，这些研究可能会改善失明眼病的预后和治疗方法。 公共卫生相关性：不适当的血管生长(血管生成)是西方世界失明眼病的主要原因。我们发现，不同个体生长血管的能力差异很大，而且是受基因控制的。我们建议在小鼠模型中确定控制血管生成的特定基因。更好地了解血管生成的基因控制是朝着盲眼疾病个性化治疗迈出的一步。

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. PUBLIC HEALTH RELEVANCE: Inappropriate blood vessel growth (angiogenesis) is the major cause of blinding eye disease in the western world. We have discovered that the ability to grow blood vessels differs significantly among individuals and is genetically controlled. We propose to identify the specific genes controlling angiogenesis in a mouse model. Better understanding of the genetic control of angiogenesis is a step toward personalizing treatments for blinding eye diseases.