CNTF and retinal degeneration: the role of Muller cells

CNTF 和视网膜变性：Muller 细胞的作用

• 批准号: 8013790
• 负责人: RONG WEN
• 金额: $ 36.35万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8013790
• 关键词: Affect; Behavior; Behavior Control; Blindness; Cellular biology; Ciliary Neurotrophic Factor; Clinical; Color Visions; Data; Degenerative Disorder; Development; Environment; Inherited; Lead; Light; Mediating; Muller' s cell; Names; Natural regeneration; Nerve Degeneration; Nervous System Part; Neuroglia; Neurons; Photoreceptors; Play; Principal Investigator; Process; Research; Retina; Retinal; Retinal Cone; Retinal Degeneration; Retinitis Pigmentosa; Role; Side; clinical application; effective therapy; interest; light effects; neuroprotection; photoreceptor degeneration; programs; release factor; research study; retinal rods

DESCRIPTION (provided by applicant): Our long-term objectives are to understand the mechanism of Muller cell-photoreceptors interaction and to develop new strategies of neuroprotection for treating retinal degenerations. Retinal degenerations are a major cause of blindness for which no effective treatments are available. It is estimated that one in 3,500 to 4,000 people is affected by retinitis pigmentosa, a heterogeneous group of inherited retinal degenerative disorders. The major manifestation of retinitis pigmentosa is progressive degeneration of photoreceptors. We have two significant findings recently. One is the discovery that CNTF modulates the activities of photoreceptors. Another is that CNTF promotes regeneration of cone inner/outer segments and reverses cone's degenerating process. The effects of CNTF are likely mediated by Muller cells. The similarity between CNTF effects and light-induced photoreceptor plasticity lead us to believe that the latter is also mediated by Muller cells. We therefore hypothesize that Muller cells play a central role in controlling the behavior of photoreceptors. This proposal contains five Specific Aims. The first two focus on characterization of CNTF- and light-induced changes in rods. The third Specific Aim is to characterize secondary cone degeneration and the capability of CNTF to reverse the degenerative process. Specific Aim four will provide direct evidence to prove the central role of Muller cells in modulating the behavior of photoreceptors. In Specific Aim five, we want to identify a putative factor that Muller cells release to communicate with photoreceptors. Results from this proposal would have important implications both in retinal cell biology and in potential clinical application of CNTF for retinal neurodegeneration. Data from our proposed experiments would enhance our understanding of the role of Muller cells in the retina. The glia-neuron interaction in maintaining neurons at an optimal level of responsiveness in a changing environment may be pertinent to other parts of the nervous system. On the practical side, a better understanding of the mechanism of action will be essential for the development of CNTF for clinical use. Our demonstration that CNTF promotes regeneration of cone inner/outer segments would be of great clinical interest, since cones are the photoreceptors responsible for central and color vision. The identification of the putative soluble factor released from Muller cells would be the first step to develop it for clinical use.

描述（由申请人提供）：我们的长期目标是了解米勒细胞-光感受器相互作用的机制，并开发治疗视网膜变性的新的神经保护策略。视网膜变性是导致失明的主要原因，目前尚无有效的治疗方法。据估计，每 3,500 至 4,000 人中就有一人患有色素性视网膜炎，这是一组异质性遗传性视网膜退行性疾病。视网膜色素变性的主要表现是感光细胞进行性变性。我们最近有两个重要发现。一是发现 CNTF 调节光感受器的活动。另一个是CNTF促进视锥细胞内/外节的再生并逆转视锥细胞的退化过程。 CNTF 的作用可能是由 Muller 细胞介导的。 CNTF 效应与光诱导的光感受器可塑性之间的相似性使我们相信后者也是由 Muller 细胞介导的。因此，我们假设米勒细胞在控制光感受器的行为中发挥核心作用。该提案包含五个具体目标。前两个重点关注 CNTF 和光引起的视杆细胞变化的表征。第三个具体目标是表征继发性视锥细胞退化以及 CNTF 逆转退化过程的能力。具体目标四将提供直接证据来证明米勒细胞在调节光感受器行为中的核心作用。在具体目标五中，我们想要确定穆勒细胞释放以与光感受器通信的推定因子。该提案的结果将对视网膜细胞生物学和 CNTF 治疗视网膜神经变性的潜在临床应用产生重要影响。我们提出的实验数据将增强我们对米勒细胞在视网膜中作用的理解。在不断变化的环境中维持神经元处于最佳反应水平的神经胶质-神经元相互作用可能与神经系统的其他部分有关。在实践方面，更好地了解作用机制对于开发临床应用的 CNTF 至关重要。我们证明 CNTF 促进视锥细胞内/外节的再生将具有很大的临床意义，因为视锥细胞是负责中枢视觉和色觉的光感受器。鉴定 Muller 细胞释放的假定可溶性因子将是开发其临床应用的第一步。

项目成果

Glutathione S-transferase pi isoform (GSTP1) expression in murine retina increases with developmental maturity.

小鼠视网膜中谷胱甘肽 S-转移酶 pi 同种型 (GSTP1) 的表达随着发育成熟而增加。

• DOI: 10.1007/978-1-4614-3209-8_4
• 发表时间: 2014
• 期刊: Advances in experimental medicine and biology
• 作者: Lee,Wen-Hsiang;Joshi,Pratibha;Wen,Rong
• 通讯作者: Wen,Rong

Oncostatin M protects rod and cone photoreceptors and promotes regeneration of cone outer segment in a rat model of retinal degeneration.

• DOI: 10.1371/journal.pone.0018282
• 发表时间: 2011-03-30
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Xia X;Li Y;Huang D;Wang Z;Luo L;Song Y;Zhao L;Wen R
• 通讯作者: Wen R

CNTF mediates neurotrophic factor secretion and fluid absorption in human retinal pigment epithelium.

• DOI: 10.1371/journal.pone.0023148
• 发表时间: 2011
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Li R;Wen R;Banzon T;Maminishkis A;Miller SS
• 通讯作者: Miller SS

Genetic ablation of Pannexin1 protects retinal neurons from ischemic injury.

• DOI: 10.1371/journal.pone.0031991
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Dvoriantchikova G;Ivanov D;Barakat D;Grinberg A;Wen R;Slepak VZ;Shestopalov VI
• 通讯作者: Shestopalov VI