The Role of sFlt in Corneal Avascularity

描述（由申请人提供）：角膜的无血管性对于视觉轴的光学透明度是必要的。威胁视力的角膜血管生成可由疾病、衰老、感染或创伤引起。角膜的生理无血管性的基础仍有待阐明。本研究将利用RNA干扰这一具有发展前景的新型高效特异性分子技术来阐明正常角膜血管的介质和机制。我们假设角膜血管至少部分是由细胞外可溶性VEGF受体-1 （sVEGFR-1）维持的。严格确定成人角膜血管是否需要sFlt-1。2. 确定角膜上皮中sFlt-1的选择性基因消融是否诱导角膜血管化。3. 测定sFlt-1在Pax6和角膜自发血管化小鼠中的表达谱，以及sFlt-1是否能恢复Pax61和角膜自发血管化小鼠的角膜血管。这一调查方向将与公共卫生具有广泛的相关性。在癌症、黄斑变性和糖尿病中，角膜通常被用作测试抗血管生成疗法疗效的平台。了解角膜如何正常维持其无血管性的分子基础将对这种抗血管生成功效研究的依赖和有效性产生重大影响。此外，sVEGFR-1在先兆子痫、狼疮和某些肾病中起致病作用。我们开发的抗VEGFR-1的siRNA可能最终有益于这些疾病的治疗，并且它也可能在促进有益的血管生成（例如中风和心脏病）方面证明有价值。

DESCRIPTION (provided by applicant): Avascularity of the cornea is necessary for optical transparency in the visual axis. Vision-threatening corneal angiogenesis can be caused by diseases, aging, infection, or trauma. The basis of the cornea's physiological avascularity remains to be elucidated. This proposal will apply RNA interference, a promising new efficient & specific molecular technology that targets specific mRNAs, to elucidate mediators and mechanisms of normal corneal avascularity. We hypothesize that corneal avascularity is maintained at least in part by extracellular soluble VEGF receptor-1 (sVEGFR-1) Our specific aims are to test the hypotheses that: 1. To rigorously determine if adult corneal avascularity requires sFlt-1. 2. To determine whether selective genetic ablation of sFlt-1 in the corneal epithelium induces corneal vascularization. 3. To determine the expression profile of sFlt-1 in Pax6 and cornl mice with spontaneous corneal vascularization and whether sFlt-1 can restore corneal avascularity in Pax61 and cornl in these mice. This line of inquiry will have broad relevance to public health. The cornea is commonly used as a platform for testing the efficacy of anti-angiogenic therapies for use in cancer, macular degeneration, and diabetes. Understanding the molecular basis of how the cornea normally maintains its avascularity will have significant ramifications for the reliance on and validity of such anti-angiogenesis efficacy studies. Furthermore, sVEGFR-1 plays a pathogenic role in pre-eclampsia, lupus, and certain nephropathies. Our development of an siRNA against VEGFR-1 may eventually be of benefit for the management of these disorders, and it may also prove valuable in promoting beneficial angiogenesis, e.g., in stroke & heart disease.