CELLULAR AND MOLECULAR MECHANISMS IN RETINAL DETACHMENT

神经视网膜与邻近的视网膜色素脱离 上皮（RPE）导致光感受器的物理分离 细胞层从RPE的顶面，扩大的细胞层， 光感受器间空间（即视网膜下腔），以及伴随的 光感受器间基质的生化组成的变化 （IPM）。它还引发了一系列复杂的细胞和分子 视网膜和RPE细胞的变化（参见Fisher和安德森，1994）。 它可能会阻碍离子和代谢物的正常转移，并释放 或激活内源性调节因子。它会触发一种渐进的 光感受器细胞的退化，并且它诱导快速增殖的 非神经元视网膜细胞的反应，这是高度相似的， 伴随脑损伤的反应性神经胶质增生。迅速重新贴壁 视网膜和RPE层可导致视网膜色素上皮细胞的阻滞和/或部分阻滞， 逆转这些异常，虽然细胞恢复， 不完全和慢性视力缺陷通常持续存在。没有 药物治疗，可以防止，逮捕，或减少 退行性和增生性变化伴随脱离或其他 获得性视网膜变性然而，它们的最终发展可能 可以预见的是， 负责维持正常的视网膜粘连，维持 感光细胞存活，维持有丝分裂静止，和 阻止反应性神经胶质增生这提供了一个令人信服的理由， 检查粘附和调节分子的功能， 通常存在于视网膜中，并且有可能影响 伴随视网膜损伤的分子事件，如脱离。 在这项提案中，重点是三个这样的分子：玻连蛋白 受体（VnR），来自整联蛋白超家族的粘附受体;和 两种生长因子，转化生长因子-β（TGF-β），和 碱性成纤维细胞生长因子（bFGF），这两者都被认为是 调节大脑中伤口愈合和疤痕形成的各个方面。的 在细胞表面表达的整合素的亚基组成 将识别和表征IPM的边界。参与 这种整合素及其IPM配体在视网膜粘连中的作用将是 使用体外和体内粘附测定进行评估。二是 将评价TGF-β 1、TGF-β 2、TGF-β 3亚型的功能 视网膜脱离引起的反应性神经胶质增生。 最后，将比较视网膜细胞对bFGF的加工， 设计用于诱导光感受器变性的条件（即， 脱离）和引发感光细胞“拯救”。为实现这些 三个目标，新的见解应该获得视网膜的动态 对损伤的反应，并进入负责维持 正常视网膜粘连

Detachment of the neural retina from the adjacent retinal pigment epithelium (RPE) results in physical separation of the photo receptor cell layer from the apical surface of the RPE, an expansion of the interphotoreceptor space (ie the subretinal space), and a concomitant change in the biochemical composition of the interphotoreceptor matrix (IPM). It also initiates a complex series of cellular and molecular changes in both retinal and RPE cells (see Fisher and Anderson, 1994). It may impede the normal transfer of ions and metabolites, and liberate or activate endogenous regulatory factors. It triggers a progressive degeneration of photoreceptor cells, and it induces a rapid proliferative response in non-neuronal retinal cells that is highly similar to the reactive gliosis that accompanies brain injury. Prompt reapposition of the retina and RPE layers can result in the arrest and/or partial reversal of some of these abnormalities, although cellular recovery is incomplete and chronic visual deficits usually persist. There are no pharmacologic treatments that can prevent, arrest, or reduce the degenerative and proliferative changes that accompany detachment or other acquired retinal degenerations. Their eventual development, however, may be predictably linked to the identification of the molecular mechanisms responsible for maintaining normal retinal adhesion, sustaining photoreceptor cell survival, maintaining mitotic quiescence, and arresting reactive gliosis. This provides a compelling rationale to examine the functions of adhesion and regulatory molecules that are normally present in the retina, and that have the potential to influence the molecular events that accompany retinal injuries such as detachment. In this proposal, the focus is on three such molecules: the vitronectin receptor (VnR), an adhesion receptor from the integrin superfamily; and two growth factors, transforming growth factor-beta (TGF-(Beta), and basic fibroblast growth factor (bFGF), both of which are thought to regulate aspects of wound healing and scar formation in the brain. The subunit composition of the integrins expressed on the surfaces of cells bordering the IPM will be identified and characterized. The involvement of this integrin(s) and its IPM ligand(s) in retinal adhesion will be assessed using in vitro and in vivo adhesion assays. Second, the function(s) of TGF-Beta1, TGF-Beta2, TGF-Beta3 isoforms will be evaluated in the context of reactive gliosis induced by retinal detachment. Finally, the processing of bFGF by retinal cells will be compared under conditions designed to induce photoreceptor degeneration (i.e. detachment) and to elicit photoreceptor cell "rescue". In pursuing these three aims, new insights should be gained into the retina's dynamic response to injury, and into the mechanisms responsible for maintaining normal retinal adhesion.