Treatment of Ocular Neovascularization by Inhibitors

抑制剂治疗眼部新生血管

• 批准号: 6518719
• 负责人: PETER LOUIS GEHLBACH
• 金额: $ 20.76万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6518719
• 关键词: amacrine cells; angiogenesis; angiogenesis inhibitors; angiostatins; enzyme linked immunosorbent assay; fluorescence microscopy; gene expression; genetically modified animals; immunocytochemistry; laboratory mouse; light microscopy; nonhuman therapy evaluation; pathologic process; polymerase chain reaction; retinal ganglion; retinal pigment epithelium; southern blotting; transfection /expression vector; transforming growth factors; uvea disorder; vascular endothelial growth factors; visual photoreceptor

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.

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 每年都需要新的治疗方法。血管抑制素和内皮抑素 是较大蛋白质的蛋白水解片段，已被证明可以抑制 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-b I (TGFP 1) 已证明在某些情况下可以抑制血管生长。我们假设 血管抑制素、内皮抑制素、PEDF 和/或 TGFP 1 在眼睛中的表达将 抑制视网膜和/或脉络膜 NV。为了检验这个假设，我将表达 转基因小鼠中的每种蛋白质并比较转基因阳性小鼠 在 3 个眼 NV 模型中与同窝对照。我也会进行类似的操作 使用眼内注射腺病毒（AV）的小鼠进行实验 或腺相关病毒 (AAV) 载体，其中包含 4 种病毒之一的构建体 蛋白质，一种直接应用于临床的方法。研究培训将 重点详细了解眼部 NV 的发病机制 在 Wilmer 研究所的 Peter Campochiaro 的指导下以及分子生物学 AAV 由佛罗里达大学 William Hauswirth 领导。临床培训 将专注于视网膜下手术，利用的技术将用于 基因转移至人类视网膜和 RPE。该项目应提供 重要的新信息，同时为我提供成为成为 利用基因疗法进行眼部 NV 领域的独立研究者 方法。它还将为我提供临床培训，最终 将知识转化为患者的新疗法。