Muller cell activation and remodeling in AMD.

AMD 中的 Muller 细胞激活和重塑。

• 批准号: 10330578
• 负责人: Malia Michelle Edwards
• 金额: $ 39.71万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10330578
• 关键词: Acute; Address; Affect; Age related macular degeneration; Amyloid beta-Protein; Anterior; Area; Atrophic; Blindness; Cell Culture Techniques; Cell Proliferation; Cell membrane; Cells; Cellular Morphology; Cicatrix; Complex; Data; Developed Countries; Disease; Disease Progression; Drusen; Exudative age-related macular degeneration; Eye; Functional disorder; Future; Geographic Locations; Glial Fibrillary Acidic Protein; Glutamate-Ammonia Ligase; Glutamine; Homeostasis; Human; In Vitro; Incidence; Inflammation; Inflammatory; Ions; Knowledge; Life Expectancy; Membrane; Mesenchymal; Metabolic; Modeling; Muller' s cell; Neuroglia; Pathology; Phenotype; Photoreceptors; Play; Process; Rattus; Reporting; Research; Retina; Retinal Diseases; Role; Stimulus; Structure of retinal pigment epithelium; Synapses; Testing; Thick; Touch sensation; Transforming Growth Factor beta; Treatment Efficacy; cell motility; cell type; cytokine; exosome; experimental study; extracellular vesicles; geographic atrophy; glial activation; migration; neurotrophic factor; new therapeutic target; novel; oxidized lipid; prevent; protein expression; response; retinal neuron; sodium iodate; stem cell therapy; therapeutic target; tissue degeneration; tissue/cell culture; vesicular release

Age-related macular degeneration (AMD) is a complex, multifactorial disease. I have recently reported subretinal Müller cell membranes in areas of geographic atrophy (GA). These membranes closely mimic areas of retinal pigment epithelial cells (RPE) and choriocapillaris loss. I have also observed Müller cells anterior to drusen expressing glial fibrillary acidic protein (GFAP) and appearing to migrate to the ONL in eyes with AMD. These data indicate Müller cell activation and remodeling in AMD. The stimuli for and consequences of these changes, however, are not understood. We hypothesize that changes to the subretinal milieu in non-neovascular AMD stimulate Müller cell activation and remodeling that exacerbates AMD pathology. The first Aim of this proposal will investigate how Müller cells are affected by subretinal changes that occur in AMD. We will investigate Müller cell morphological and metabolic changes anterior to drusen in human donor eyes with AMD. We will then evaluate the Müller cell response to drusen components, amyloid beta and oxidized lipids, in vitro. The second subAim of Aim 1 will determine the effect that RPE cells exert on Müller cells. While these cells are normally separated by the photoreceptor segments, subretinal pathology as well as their abnormal migration and extension allows them to touch in eyes with AMD. We will analyze the RPE influence on Müller cells using human AMD tissue and cell culture experiments. The second proposed Aim focuses on how Müller cells in the subretinal space affect neighboring cells. We will first investigate how Müller cells affect RPE cells using cell culture experiments. We will also investigate extracellular vesicle release by Müller cells and, if present, determine what effect these have on RPE cells. We will also investigate the composition of the subretinal glial membranes that we have observed in GA. Since it is not possible to determine in human retinas how early in the disease process glia intrude the subretinal space, we have developed a rat model with focal RPE cell atrophy. We will also determine whether these glial membranes form a scar which will prevent the flow of material, including future stem cell therapy, from the retina to subretinal space. Finally, we will inhibit the membrane and determine how this affects disease progression in our rat model of RPE atrophy. These studies will determine the role glia play in AMD pathology, potentially identifying novel treatments. By investigating extracellular vesicle and exosome release from Müllers, our studies will identify how Müller cells interact with other cell types in the normal and diseased retina.

与年龄相关的黄斑变性（AMD）是一种复杂的多因素疾病。我最近有 报道了地理萎缩（GA）区域的视网膜下müller细胞膜。这些膜 紧密模仿视网膜色素上皮细胞（RPE）和脉络膜毛细血管丧失的区域。我也有 观察到表达神经纤维纤维酸性蛋白（GFAP）的drusen前方的müller细胞，并且出现 用AMD迁移到ONL。这些数据表明Müller细胞激活和重塑 AMD。但是，尚不了解这些变化的刺激和后果。我们 假设在非血管AMD中对视网膜下环境的变化刺激müller细胞 激活和重塑加剧了AMD病理学。 该提案的第一个目的将调查穆勒细胞如何受到视网膜下变化的影响 发生在AMD中。我们将研究Müller细胞的形态和代谢变化。 人类捐助者的眼睛与AMD。然后，我们将评估Müller细胞对Drusen成分的响应， 淀粉样蛋白β和氧化的脂质，体外。 AIM 1的第二个子将决定 RPE细胞施加在müller细胞上。这些细胞通常被感光器分离 段，视网膜下病理以及它们的绝对迁移和扩展使他们可以接触 在AMD的眼睛中。我们将使用人AMD组织和细胞分析RPE对Müller细胞的影响 培养实验。 第二个提出的目标重点是视网膜下空间中的müller细胞如何影响相邻 细胞。我们将首先研究Müller细胞如何使用细胞培养实验影响RPE细胞。我们将 还研究穆勒细胞释放细胞外囊泡，如果存在，请确定这些影响 具有RPE细胞。我们还将研究我们的视网膜下神经胶质膜的组成 在GA中观察到。由于无法在人视网膜中确定疾病早期 过程神经胶质侵入视网膜下空间，我们开发了一种具有局灶性RPE细胞萎缩的大鼠模型。 我们还将确定这些神经胶质膜是否形成疤痕，以防止流动 从视网膜到视网膜下空间，包括未来的干细胞疗法，包括未来的干细胞疗法。最后，我们将抑制 膜并确定这如何影响我们的RPE萎缩大鼠模型中的疾病进展。 这些研究将确定神经胶质在AMD病理学中的作用，并有可能识别新型 治疗。通过研究细胞外囊泡和从müllers释放的外泌体释放，我们的研究将 确定在正常视网膜和解散的视网膜中如何与其他细胞类型相互作用。