INDUCED APOPTOSIS IN AGE RELATED MACULAR DEGENERATION

描述：（申请人的描述） 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）、糖尿病性视网膜病变和视网膜病变 早产 AMD是西方世界失明的主要原因， 60岁以上的人。 因为很大一部分人口 这是一个严重的威胁， 老年人的生活。 在AMD患者中，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， 通过检测两种分子Fas（CD 95）和FasL的功能， （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）阻止 损害视力的新Fas+视网膜下血管的生长和发育。 本提案中描述的研究旨在彻底了解 Fas/FasL和细胞凋亡在AMD发病中的作用 我们提出了五个目标。 目的1：探讨Fas/FasL在小鼠CNV中的作用 使用正常、Fas和FasL缺陷型小鼠的模型。 在目标2中，我们将研究细胞 内皮细胞来源于脉络膜，并比较这些内皮细胞 细胞来源于其他领域。 我们将检查细胞死亡，增殖， 和分化，并表征Fas的作用。 抗原在这些过程中。 目标3将包含探索 FasL在RPE细胞上的功能，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，这些功能在 控制CNV。 目的4将探索CNV的潜在治疗方式 应用我们已经获得的关于FasL调节的知识， 表达到动物模型。 最后，目标5中的研究将评估 AMD患者的临床标本中Fas/FasL的表达。 我们的研究 应该能提供重要的见解， 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.