The Role of sFlt in Corneal Avascularity

描述(申请人提供)：角膜的无血管是视觉轴上光学透明所必需的。影响视力的角膜血管生成可由疾病、衰老、感染或创伤引起。角膜生理性无血管的基础仍有待阐明。这项建议将应用RNA干扰，这是一种有前景的有效和特异的新分子技术，针对特定的mRNAs，以阐明正常角膜无血管的介体和机制。我们假设角膜无血管的维持至少部分是通过细胞外可溶性血管内皮生长因子受体-1(sVEGFR-1)来维持的，我们的具体目的是检验以下假设：1.严格确定成人角膜无血管是否需要sFlt-1。2.确定选择性基因消融角膜上皮细胞中sFlt-1是否诱导角膜新生血管形成。3.检测sFlt-1在Pax6和Corn1小鼠自发性角膜新生血管中的表达情况，以及sFlt-1能否恢复Pax61和Corn1小鼠的角膜无血管状态。这一调查路线将与公共卫生具有广泛的相关性。角膜通常被用作测试用于癌症、黄斑变性和糖尿病的抗血管生成疗法的有效性的平台。了解角膜如何正常维持其无血管的分子基础，将对此类抗血管生成功效研究的可靠性和有效性具有重要的影响。此外，sVEGFR-1在先兆子痫、狼疮和某些肾病中起致病作用。我们开发的针对VEGFR-1的siRNA最终可能对这些疾病的治疗有益，它也可能被证明在促进有益的血管生成方面有价值，例如在中风和心脏病中。

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.