Regenerative potential of retinal Muller glial cells

视网膜米勒胶质细胞的再生潜力

• 批准号: 7761723
• 负责人: Ross Anthony Poche
• 金额: $ 5.05万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7761723
• 关键词: Alzheimer' s Disease; Behavior; Biological Models; Blindness; Blood Vessels; Cell Cycle; Cells; Cicatrix; Cognitive; Complex; Data; Disease; Environment; Event; Exhibits; Figs - dietary; Generations; Genetic; Gliosis; Goals; Heart; Human; Image; Intermediate Filaments; Label; Life; Light; Mammals; Maps; Mitosis; Mitotic; Molecular; Mus; Mutant Strains Mice; Natural regeneration; Nerve Degeneration; Neuroglia; Neurons; Outer Limiting Membrane; Parkinson Disease; Population; Regenerative Medicine; Research; Research Proposals; Retina; Retinal; Sensory; System; Tamoxifen; Testing; Therapeutic; Time; Transplantation; Vimentin; cell behavior; in vivo; motor disorder; nervous system disorder; recombinase; regenerative; repaired; research study; response; retinal damage; retinal neuron

DESCRIPTION (provided by applicant): The objective of this research proposal is to determine the potential of the mammalian retina for repair via endogenous mechanisms. In response to retinal damage, Muller glial (MG) cells of several vertebrate model systems have been shown to give rise to new retinal neurons. However, in mammals, there is a paucity of data directly testing the regenerative capacity of MG cells in vivo. Our central hypothesis is that, in response to retinal damage, mature mouse MG cells possess the ability to re-enter the cell cycle and trans-differentiate into retinal neurons. The overall goal of this proposal is to test this hypothesis by performing genetic, Cre-loxP fate mapping experiments and time lapse imaging. Aim 1. Determine the capacity of mouse Muller glial cells to give rise to mature retinal neurons within specific environmental contexts. We will test the hypothesis that retinal Muller glial (MG) cells have the ability to regenerate retinal neurons by chemically inducing neuronal degeneration and performing in vivo Cre-loxP fate-mapping experiments. We will also test the hypothesis that MG cell regenerative potential is significantly hindered as a consequence of a non-permissive retinal environment due to glial scarring. Here, we will perform the same fate-mapping experiment, but within the genetic background of Vimentin-/-; Gfap-/- mutant mice known to exhibit a retinal environment substantially more supportive of neuronal transplantation. Aim 2. Elucidate the cellular mechanisms of the Muller glial response to retinal damage and subsequent trans-differentiation events. We hypothesize that, in response to damage, a discrete subset of MG cells re-enter the cell cycle and translocate apically toward the outer limiting membrane of the retina where they undergo mitosis before translocating to the appropriate lamina as differentiating neurons. To test this hypothesis, we will perform live imaging of damage-induced retinal explants in which MG cells are fluorescently labeled. RELEVANCE Neuronal degeneration lies at the heart of a spectrum of debilitating human cognitive and motor diseases including Alzheimer's and Parkinson's disease as well as sensory diseases such as blindness. By characterizing cell populations within the retina, which have the ability to generate new neurons, therapeutic approaches could be employed to harness the ability of these cells to cure human neurological diseases.

描述（由申请人提供）：本研究计划的目的是确定通过内源性机制修复哺乳动物视网膜的潜力。在对视网膜损伤的反应中，Muller胶质细胞（MG）在几种脊椎动物模型系统中已经被证明产生新的视网膜神经元。然而，在哺乳动物中，缺乏直接测试MG细胞在体内再生能力的数据。我们的中心假设是，在视网膜损伤的反应中，成熟的小鼠MG细胞具有重新进入细胞周期并转分化为视网膜神经元的能力。本提案的总体目标是通过进行遗传，Cre-loxP命运映射实验和延时成像来验证这一假设。目的1。确定小鼠Muller胶质细胞在特定环境下产生成熟视网膜神经元的能力。我们将通过化学诱导神经元变性和体内Cre-loxP命运定位实验来验证视网膜Muller胶质（MG）细胞具有再生视网膜神经元能力的假设。我们还将验证一个假设，即由于神经胶质瘢痕形成的不允许的视网膜环境，MG细胞的再生潜力受到显著阻碍。在这里，我们将进行相同的命运定位实验，但在遗传背景Vimentin-/-；已知Gfap-/-突变小鼠表现出更支持神经元移植的视网膜环境。目标2。阐明Muller胶质细胞对视网膜损伤和随后的反分化事件反应的细胞机制。我们假设，作为对损伤的反应，MG细胞的一个离散子集重新进入细胞周期，并向视网膜的外限制膜顶端移位，在那里它们进行有丝分裂，然后作为分化的神经元转移到适当的层。为了验证这一假设，我们将对损伤诱导的视网膜外植体进行实时成像，其中MG细胞被荧光标记。神经元变性是一系列使人衰弱的人类认知和运动疾病的核心，包括阿尔茨海默病和帕金森病，以及失明等感觉疾病。通过表征视网膜内具有产生新神经元能力的细胞群，可以采用治疗方法来利用这些细胞的能力来治愈人类神经系统疾病。