CELL BIOLOGY OF EXPERIMENTAL RETINAL DETACHMENT AND REAT

描述(改编自申请者的摘要)：神经脱离 视网膜色素上皮形成的视网膜引发一系列事件 通过激活早期反应基因，可以在几分钟内检测到。这 导致视网膜脱离的视网膜病变(RD)，一系列特殊细胞 在过去的资助期内已详细说明的活动。这包括 某些受体因细胞凋亡而死亡--生存的“解构” 光感受器细胞因此它们呈现出更原始的结构，在 光感受器和Muller细胞(以及其他视网膜细胞)中的基因表达 视网膜中所有非神经细胞类型的增殖，以及 穆勒细胞在正常视网膜内外的显著生长 边界。即使在成功重接后，视力恢复也往往较差 尤其是在涉及黄斑的情况下。视网膜脱离有 严重的视觉后果，是几种视网膜疾病的并发症 也是治疗致盲疾病的实验性疗法的一部分：中心凹 移位、视网膜移植和视网膜下注射载体 视网膜细胞的转染法。因此，定义了生物机制 了解脱离和重新附着的反应，并找到方法 优化视网膜的恢复似乎具有明显的医学意义。 这一续订申请使用了研究人员建立的猫模型 脱离/重新附着以研究重新附着停止或反转的能力 剥离引起的基本细胞变化；进一步研究 CNTF和高氧等神经营养因子作为缓解退行性变的方法 脱离或促进附着后恢复的效果；并研究 IL-1及其受体拮抗剂(IL-1ra)在应激反应中的作用 超然。已知视锥感光细胞对 分离，但对猫视锥的研究很困难，而且 在灵长类动物中令人望而却步。申请人建议开发一种 加州地松鼠的脱离/再附着模型，一种具有 视网膜约有85%的视锥细胞受损，这是很容易获得的，并且 在视觉研究中得到了广泛的应用。申请者将决定 使用ERG测量作为一种关联的方法的可行性 视锥细胞感光细胞的生理和结构恢复。申请人 相信这个模型的使用将有助于理解 并更好地确定治疗方法(如神经营养因子、高氧血症) 减轻视杆细胞占主导地位的视网膜脱离的影响将在 视锥占优势的视网膜也是如此。申请人相信这些信息将 更好地了解视网膜对损伤的反应，并可能 导致了改善人类视力恢复的方法。

DESCRIPTION (Adapted from the applicant's abstract): Detachment of the neural retina from the retinal pigmented epithelium induces a cascade of events detectable within minutes through the activation of early response genes. This leads to the "retinopathy of detachment" (RD), a series of specific cellular events which have been detailed over the past funding period. This includes the death of some receptors by apoptosis, the "deconstruction" of surviving photoreceptor cells so that they assume a more primitive structure, changes in gene expression in photoreceptors and Muller cells (and other retinal cells as well), the proliferation of all non-neural cell types in the retina, and significant growth of Muller cells within and outside their normal retinal boundaries. Visual recovery even after successful reattachment is often less than optimal, especially if the macula is involved. Retinal detachments have serious visual consequences and are a complication of several retinal diseases as well as part of experimental therapies for blinding diseases: foveal translocation, retinal transplantation and subretinal injections of vectors for transfection of retinal cells. Thus, defining the biological mechanisms underlying the responses to detachment and reattachment and finding methods to optimize recovery of the retina would seem to be of clear medical significance. This renewal application uses the investigator's established feline model of detachment/reattachment to study the ability of reattachment to stop or reverse fundamental cellular changes induced by detachment; to further study the use of neurotrophins such as CNTF and hyperoxia as ways to mitigate the degenerative effects of detachment or promote recovery after attachment; and to study the potential role of IL-1 and its receptor antagonist (IL-1ra) in the response to detachment. It is known that cone photoreceptors react differently to detachment than rods, but the study of cones in cat is difficult, and prohibitive in primates. The applicant proposes to develop a detachment/reattachment model in the California ground squirrel, a species with a retina compromised of about 85 percent cones, that is readily available, and that has been used extensively in vision research. The applicant will determine the feasibility of using ERG measures as a means of correlating the physiological and structural recovery of cone photoreceptors. The applicant believes that the use of this model will aid in understanding the responses of cones and to better determine if treatments (e.g., neurotrophins, hyperoxia) that mitigate the effects of detachments in rod-dominated retinas will do so in a cone-dominant retina as well. The applicant believes this information will provide a greater understanding of the retina's responses to injury, and may lead to ways of improving visual recovery in humans.