INDUCED APOPTOSIS IN AGE RELATED MACULAR DEGENERATION

年龄相关性黄斑变性中诱导细胞凋亡

• 批准号: 6041959
• 负责人: Thomas Almon Ferguson
• 金额: $ 34.23万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-01 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6041959
• 关键词: aging; angiogenesis; angiogenesis inhibitors; apoptosis; cell growth regulation; confocal scanning microscopy; disease /disorder model; human tissue; immunocytochemistry; laboratory mouse; macular degeneration; polymerase chain reaction; retina circulation disorder; retinal pigment epithelium; tissue /cell culture; vascular endothelium

DESCRIPTION: (Applicant's Description) Neovascularization is the major cause of vision loss in patients with age- related macular degeneration (AMD), diabetic retinopathy, and retinopathy of prematurity. AMD is the leading cause of blindness in the Western world in individuals over 60 years of age. Since a large proportion of the population is living well beyond this age, this is a significant threat to the quality of life in elderly people. In patients with AMD new vessel growth (angiogenesis) beneath the retina from the underlying choroid (choroidal neovascularization or CNV) is the major or cause of severe visual loss in these patients. We recently examined the role of apoptosis in controlling new vessel growth in the eye by examining the function of two molecules, Fas (CD95) and FasL (CD95L). Our studies revealed that FasL plays a significant role in controlling CNV, where FasL+ retinal pigment epithelial cells (RPE) prohibit the growth and development of new Fas+ subretinal vessels that damage vision. Studies described in this proposal are designed to thoroughly understand the role of Fas/FasL and apoptosis in the pathogenesis of AMD. We propose 5 aims. Aim 1 we will more completely evaluate the role of Fas/FasL in CNV in a mouse model using normal, Fas, and FasL defective mice. In Aim 2 we will study cell endothelial cells derived from the choroid and compare these to endothelial cells derived from other areas. We will examnine cell death, proliferation, and differentiation using in vitro models and characterize the role of the Fas antigen in these processes. Aim 3 will contains experiments to explore the function of FasL on RPE cells and determine how growth factors and MMP inhibitors can affect FasL function in these cells that are crucial in controlling CNV. Aim 4 will explore potential treatment modalities in CNV applying the knowledge we have gained concerning the regulation of FasL expression to the animal model. Finally, studies in Aim 5 will evaluate clinical specimens from patients AMD for Fas/FasL expression. Our studies should provide important insights into one of the leading causes of blindness in the western world.

描述：(申请人描述) 新生血管是老年患者视力丧失的主要原因- 相关性黄斑变性(AMD)、糖尿病视网膜病变和 早产儿。年，AMD是西方世界导致失明的主要原因 60岁以上的个人。因为有很大一部分人口 活得远远超过这个年龄，这是对生活质量的重大威胁 老年人的生活。AMD患者的新血管生长(血管生成) 视网膜下的脉络膜(脉络膜新生血管 或CNV)是这些患者严重视力丧失的主要或原因。我们 最近研究了细胞凋亡在控制新生血管生长中的作用 通过检测Fas(CD95)和FasL两个分子的功能来研究眼睛 (CD95L)。我们的研究表明FasL在 控制CNV，其中FasL+视网膜色素上皮细胞(RPE)禁止 新的Fas+视网膜下血管的生长和发展会损害视力。 本提案中描述的研究旨在彻底了解 Fas/FasL和细胞凋亡在AMD发病机制中的作用我们提出了五个目标。 目的1我们将更全面地评价Fas/FasL在小鼠CNV中的作用 用正常、Fas和FasL缺陷小鼠建立模型。在目标2中，我们将研究细胞 脉络膜来源的内皮细胞并与内皮细胞进行比较 来自其他区域的细胞。我们将检查9个细胞的死亡，增殖， 并利用体外模型进行分化和鉴定Fas的作用 在这些过程中的抗原。Aim 3将包含探索 FasL在RPE细胞中的作用及生长因子与基质金属蛋白酶的关系 抑制剂可以影响这些细胞中的FasL功能，而FasL功能在 控制CNV。AIM 4将探索CNV的潜在治疗方式 应用我们所获得的关于FasL调控的知识 对动物模型的表达。最后，目标5中的研究将评估 检测AMD患者临床标本中Fas/FasL的表达。我们的研究 应该对导致失明的主要原因之一提供重要的见解 在西方世界。