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Muller Cell Role in Retinal Diseases

Muller 细胞在视网膜疾病中的作用

基本信息

批准号：
7895587
负责人：
VIJAY P SARTHY
金额：
$ 34.31万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7895587
关键词：
Address Affect Age related macular degeneration Animal Model Antioxidants Biochemical Biological Biological Assay Blindness Carbon Dioxide Cell physiology Cells Cessation of life Ciliary Neurotrophic Factor Data Development Drug Metabolic Detoxication Energy Supply Eye Free Radical Scavenging Gene Expression Gene Family Genes Glutamates Growth Factor Health Homeostasis Impairment Inflammatory Investigation Knowledge Laboratories Lead Mediating Metabolic Methods Microglia Molecular Muller&apos s cell Mus Mutation Nature Neurodegenerative Disorders Neuroglia Neurons Neuroprotective Agents Neurotransmitters Nitric Oxide Pathogenesis Pathology Pathway Analysis Patients Phase I Clinical Trials Phase II Clinical Trials Photoreceptors Physiological Play Process Production Proteins Regulation Research Research Personnel Retina Retinal Retinal Cone Retinal Degeneration Retinal Diseases Retinitis Pigmentosa Role Safety Signal Transduction Sorting - Cell Movement Supporting Cell Testing Therapeutic Thick Time Tissues Vertebrate Photoreceptors Work base cell type chemokine cytokine design excitotoxicity extracellular genome-wide improved inherited retinal degeneration innovation neuronal survival neuroprotection neurotrophic factor photoreceptor degeneration prevent retinal neuron retinal rods

项目摘要

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.

莫勒细胞是脊椎动物视网膜中的主要神经胶质细胞，在维持神经元方面起着至关重要的作用。健康和运动。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，随着Moler细胞的激活，人们对随后发生的分子变化知之甚少激活，以及激活如何影响莫勒细胞在视网膜稳态和视网膜疾病中的作用发病机制。拟议的研究·旨在回答这些问题。这些研究都是在首次有可能通过开发一种利用激活的荧光来纯化Moeller细胞的方法细胞分类器。该提案有两个具体目标。第一个特定的目标是确定Modeler细胞在睫状神经营养因子介导的光感受器神经保护作用CNTF似乎是最多的有效且不依赖突变的神经保护剂，可减缓遗传性视网膜的光感受器丢失堕落的人。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，第二阶段试验正在进行中。不幸的是，我们现在还不知道CNTF是如何拯救光感受器的，但CNTF似乎可能通过刺激Muller细胞发挥作用。我们建议研究(1)CNTF是否治疗米勒细胞释放神经保护剂，防止光感受器丢失；和(2) 检测CNTF诱导小胶质细胞基因表达的变化。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作用的分子解释以及 CNTF治疗的合理依据。激活的莫勒细胞的分子特征有望导致光感受器退化的创新治疗方法，其目的是刺激莫勒细胞制造神经保护剂，防止光感受器死亡，恢复莫勒细胞的神经支持在病变的视网膜中丧失功能。