INNER RETINAL NEURONS IN NORMAL AND DEGENERATING

描述(申请人提供)：这项研究的主要目标是评估视网膜色素变性(RP)小鼠模型视网膜内部的形态和功能的完整性。RP是一组遗传性疾病，以视网膜光感受器进行性退化为特征，是世界上导致失明的主要原因之一，目前尚无有效的治疗方法。治疗这种毁灭性疾病最有希望的策略包括基因疗法、用人工假体对视网膜内部进行电刺激和细胞移植。他们的成功在一定程度上是基于这样的假设，即在感光器死亡后，内部视网膜基本上被保存下来，对残留细胞的不利影响非常有限。然而，最近的文献已经提供了明确的证据表明，在RP的动物模型中，视网膜内细胞经历了严重的形态和功能变化，只有在使用选择性的研究方法(如单个细胞的可视化)时，这种变化才变得明显。 我们的长期目标是确定光感受器退行性变对其他视网膜细胞产生不良影响的确切时间序列和机制，最终完全防止它们，并确定抢救治疗的最佳时间窗口。 本项目基于对RP独特小鼠模型的视网膜组织的解剖学、电生理学和发育研究，该模型复制了一些最常见的人类疾病形式。现代技术结合在一起，揭示了疾病进展不同阶段视网膜内细胞的形态和功能异常。来自死后RP捐献者的人视网膜也被显微镜检查。我们的目标是揭示视网膜内部的异常，这种异常在小鼠和人类的视网膜变性中都很常见，并且独立于潜在的遗传原因而发生。这对于设计不依赖突变的疗法非常重要。

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.