Muller Cell Role in Retinal Diseases

MOiler细胞是脊椎动物视网膜中的主要胶质细胞，在维持神经元的功能中起重要作用。 健康和活动。最近对视网膜神经胶质细胞的研究也表明，几乎每一种视网膜疾病都与 目前，人们对MOILER细胞的“激活”后发生的分子变化知之甚少。 激活，以及激活如何影响视网膜稳态和视网膜疾病中的MOiler细胞作用 发病机制这些研究旨在回答这些问题。这些研究是在 通过开发一种使用荧光活化的方法来纯化MOILER细胞， 细胞分类器。该提案有两个具体目标。第一个具体的目的是确定MOILER细胞在 睫状神经营养因子（CNTF）介导的光感受器神经保护。CNTF似乎是最 一种有效的非突变性神经保护剂，可减缓遗传性视网膜病变中的感光细胞丧失， 退化最近，一项I期临床试验证实了CNTF治疗视网膜色素变性（RP）的安全性 患者，II期试验正在进行中。不幸的是，我们不知道CNTF是如何拯救光感受器的， 但CNTF可能通过刺激Muller细胞发挥作用。我们建议研究（1）CNTF是否处理 Muller细胞释放神经保护剂，其用于防止感光细胞损失;和（2） 确定CNTF诱导的小胶质细胞基因表达变化。这些发现应该有助于剖析莫勒 细胞-小胶质细胞-光感受器相互作用;因此，提供了CNTF作用的分子解释， CNTF治疗的合理依据。活化的MOiler细胞的分子表征可以预期导致 光感受器变性的创新治疗方法，其目的是刺激MOiler细胞， 产生神经保护剂，防止感光细胞死亡，并恢复MOILER细胞的神经支持 患病视网膜的功能丧失。

MOiler cells, the predominant glial cells in the vertebrate retina, play an essential role in maintaining neuronal health and activity. Recent work on retinal glia has also shown that virtually every retinal disease is associated with 'activation' of MOiler cells At present very little is known about what molecular changes occur following activation, and how activation impacts on MOiler cell role in retinal homeostasis and retinal disease pathogenesis. The proposed studies ·are designed to answer these questions. These studies are made possible for the first time by the development of a method to purify MOiler cells using Florescence Activated Cell Sorter. The proposal has two specific aims. The first specific aim is to determine the role of MOiler cells in photoreceptor neuroprotection mediated by Ciliary neurotrophic factor (CNTF). CNTF appears to be the most effective and mutation-independent, neuroprotective agent that slows photoreceptor loss in inherited retinal degenerations. Recently, a phase I clinical trial demonstrated the safety of CNTF in retinitis pigmentosa (RP) patients, and phase II trials are underway. Unfortunately, we do not now how CNTF rescues photoreceptors, but it appears that CNTF might act by stimulating Muller cells. We propose to examine (1) whether CNTFtreated Muller cells release neuroprotective agents, which act to prevent photoreceptor loss; and (2) to determine gene expression changes induced in microglia by CNTF. These findings should help dissect MOiler cell-microglia-photoreceptor interactions; thus, providing a molecular explanation for CNTF action as well as a rational basis for CNTF therapy. Molecular characterization of activated MOiler cells can be expected to lead to innovative, therapeutic treatments for photoreceptor degenerations, whose aim is to stimulate MOiler cells to produce neuroprotective agents that prevent photoreceptor death, and to restore MOiler cell's neuronsupportive functions lost in the diseased retina.