INDUCED APOPTOSIS IN AGE RELATED MACULAR DEGENERATION

描述：（申请人的描述） 新生血管形成是老年患者视力丧失的主要原因 相关黄斑变性 (AMD)、糖尿病性视网膜病变和视网膜病变 早产。 AMD 是西方世界导致失明的主要原因 60岁以上的个人。 由于很大一部分人口 生活质量远远超过这个年龄，这对生活质量构成重大威胁 老年人的生活。 AMD 患者新血管生长（血管生成） 位于视网膜下方的脉络膜（脉络膜新生血管） 或CNV）是这些患者严重视力丧失的主要原因。 我们 最近研究了细胞凋亡在控制新血管生长中的作用 通过检查 Fas (CD95) 和 FasL 这两个分子的功能来观察眼睛 （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育会损害视力。 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 5 个目标。 目标 1 我们将更全面地评估 Fas/FasL 在小鼠 CNV 中的作用 使用正常、Fas 和 FasL 缺陷小鼠建立模型。 在目标 2 中，我们将研究细胞 来自脉络膜的内皮细胞并将其与内皮细胞进行比较 来自其他区域的细胞。 我们将检查细胞死亡、增殖、 使用体外模型进行分化和分化，并表征 Fas 的作用 这些过程中的抗原。 目标 3 将包含实验来探索 FasL 对 RPE 细胞的功能并确定生长因子和 MMP 抑制剂可以影响这些细胞中的 FasL 功能，这对于 控制CNV。 目标 4 将探索 CNV 的潜在治疗方式 应用我们获得的有关 FasL 调控的知识 表达到动物模型上。 最后，目标 5 中的研究将评估 AMD 患者的临床标本的 Fas/FasL 表达。 我们的研究 应该对失明的主要原因之一提供重要的见解 在西方世界。

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.