Treatment of Ocular Neovascularization by Inhibitors

描述：（申请人摘要）视网膜和脉络膜新生血管形成 (NV)占发达国家严重视力丧失的绝大多数 因此，每年都需要新的治疗方法。血管抑素和内皮抑素 是较大蛋白质的蛋白水解片段， 小鼠肿瘤血管生成。色素上皮衍生因子（PEDF）是 由视网膜色素上皮（RPE）和眼睛的其他细胞产生 并抑制角膜NV。转化生长因子-β 1（TGF β 1）已被广泛应用于 在某些情况下被证明可以抑制血管生长。我们假设 血管抑制素、内皮抑制素、PEDF和/或TGF β 1在眼睛中的表达将 抑制视网膜和/或脉络膜NV。为了验证这一假设，我将表达 在转基因小鼠中的每一种蛋白质， 在3种眼部NV模型中与同窝对照进行比较。我将执行类似 使用眼内注射腺病毒（AV）的小鼠进行的实验 或腺相关病毒（AAV）载体，所述载体含有用于4种 蛋白质，一种直接临床应用的方法。研究培训将 重点是获得详细了解的发病机制，眼NV 在威尔默研究所的彼得·坎波奇亚罗的领导下， AAV在佛罗里达大学的William Hausperth的指导下进行。临床培训 将专注于视网膜下手术，利用技术，将用于 基因转移到人类的视网膜和RPE。该项目将提供 重要的新信息，同时为我提供必要的培训， 一个独立的研究人员在该地区的眼睛NV利用基因疗法 approach.它还将为我提供临床培训， 将这些知识转化为新的治疗方法。

DESCRIPTION: (Applicant's Abstract) Retinal and choroidal neovascularization (NV) account for a large majority of severe visual loss in developed countries each year and therefore new treatments are needed. Angiostatin and endostatin are proteolytic fragments of larger proteins that have been shown to inhibit tumor angiogenesis in mice. Pigment epithelium-derived factor (PEDF) is produced by the retinal pigmented epithelium (RPE) and other cells of the eye and inhibits corneal NV. Transforming growth factor-b I (TGFP 1) has been demonstrated to inhibit blood vessel growth in some settings. We hypothesize that expression of angiostatin, endostatin, PEDF and/or TGFP 1 in the eye will inhibit retinal and/or choroidal NV. To test this hypothesis, I will express each of these proteins in transgenic mice and compare transgene-positive mice with littermate controls in 3 models of ocular NV. I will perform similar experiments using mice that have had intraocular injection of adenovirus (AV) or adeno-associated virus (AAV) vector containing a construct for one of the 4 proteins, an approach with direct clinical application. Research training will focus on gaining a detailed understanding of the pathogenesis of ocular NV under Peter Campochiaro at the Wilmer Institute and the molecular biology of AAV under William Hauswirth at the University of Florida. Clinical training will focus on subretinal surgery utilizing techniques that will be used for gene transfer to the retina and RPE in humans. This project should provide important new information, while providing me the training necessary to become an independent investigator in the area of ocular NV utilizing a gene therapy approach. It will also provide me with clinical training to eventually translate the knowledge into new treatments for patients.