INNER RETINAL NEURONS IN NORMAL AND DEGENERATING MICE

描述（由申请方提供）：本研究的主要目的是评估视网膜色素变性（RP）小鼠模型中内层视网膜的形态和功能完整性。RP包括一组以视网膜光感受器的进行性变性为特征的遗传性疾病，并且是世界上失明的主要原因之一，没有可用的治愈方法。治疗这种毁灭性疾病的最有希望的策略包括基因治疗，人工假体和细胞移植的内层视网膜的电刺激。他们的成功部分是基于这样的假设，即在感光细胞死亡后，内层视网膜大部分被保存下来，并且对残留细胞的不利影响非常有限。然而，最近的文献提供了明确的证据，负性视网膜重塑的动物模型的RP：内部视网膜细胞发生严重的形态和功能的改变，变得明显，只有当选择性的调查方法（如可视化的个别细胞）被使用。 我们的长期目标是确定感光细胞变性对其他视网膜细胞产生不良影响的确切时间顺序和机制，最终完全预防它们，并识别救援治疗的最佳时间窗口。 本项目是基于解剖学，电生理学和发育研究的视网膜组织在独特的小鼠模型的RP，重现了一些最常见的形式的人类疾病。现代技术相结合，以揭示在疾病进展的各个阶段的视网膜内细胞的形态和功能异常。还对来自死后RP供体的人视网膜进行显微镜检查。我们的目标是揭示内部视网膜异常，这是共同的小鼠和人类形式的视网膜变性和发生独立的潜在遗传原因。这对于设计突变非依赖性疗法非常重要。

DESCRIPTION (provided by applicant): The primary objective of this study is to assess the morphological and functional integrity of the inner retina in mouse models of Retinitis Pigmentosa (RP). RP comprises a group of inherited disorders characterized by progressive degeneration of retinal photoreceptors, and represents one of the major causes of blindness in the world, with no available cure. The most promising strategies to treat this devastating disease include gene therapy, the electrical stimulation of the inner retina with artificial prostheses and cellular transplantation. Their success is partly based upon the assumption that the inner retina is largely preserved following photoreceptor death and that adverse effects upon residual cells are very limited. However, recent literature has provided clear evidence of negative retinal remodeling in animal models of RP: inner retinal cells undergo severe morphological and functional alterations that become evident only when selective methods of investigation (such as the visualization of individual cells) are used. Our long-term objective is to identify the exact time sequence and mechanisms by which photoreceptor degeneration triggers adverse effects upon other retinal cells, ultimately to prevent them completely and to recognize optimal time windows for rescue therapies. The present project is based upon anatomical, electrophysiological and developmental studies of the retinal organization in unique mouse models of RP, which reproduce some of the most frequent forms of the human disease. Modern techniques are combined to reveal morphological and functional abnormalities of inner retinal cells at various stages of the disease progression. Human retinas from postmortem RP donors are also examined microscopically. We aim at uncovering inner retinal abnormalities that are common to both mouse and human forms of retinal degeneration and occur independently of the underlying genetic cause. This is very important to design mutation-independent therapies.