Müller glia in disease and stress

米勒神经胶质细胞在疾病和压力中的作用

• 批准号: 9384308
• 负责人: YUN Zheng LE
• 金额: $ 37万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9384308
• 关键词: Address; Age related macular degeneration; Animals; Apoptosis; Biochemical; Biological Aging; Biological Preservation; Blindness; Blood; Blood Vessels; Brain-Derived Neurotrophic Factor; Cell Line; Cell Survival; Clinical Trials; Consensus; Data; Dependovirus; Development; Diabetes Mellitus; Diabetic Retinopathy; Disease; Employee Strikes; Experimental Diabetes Mellitus; Extravasation; Eye diseases; GDNF gene; Goals; Hypoxia; Inflammation; Investigational Therapies; KDR gene; Knock-out; Knockout Mice; Knowledge; Lesion; Mediating; Modeling; Molecular; Muller' s cell; Mus; Nerve Degeneration; Neurons; Neuroprotective Agents; Outcome; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Production; Public Health; Publications; Recombinant Proteins; Retina; Retinal; Retinal Degeneration; Retinal Diseases; Retinopathy of Prematurity; Role; Safety; Signal Transduction; Source; Stress; Supporting Cell; Testing; Therapeutic; Thinness; Treatment Factor; United States National Institutes of Health; Ursidae Family; VEGFA gene; Vascular Endothelial Growth Factors; Virulence Factors; Vision; Visual Acuity; base; density; design; diabetic; experimental study; glial cell-line derived neurotrophic factor; improved; in vivo; insight; mouse model; neuroprotection; neurotrophic factor; neutralizing antibody; pre-clinical; retinal neuron; small hairpin RNA

Vascular endothelial growth factor (VEGF) is a major pathogenic factor for wet age-related macular degeneration (AMD) and diabetic retinopathy (DR), leading causes of blindness in the US. Intensive studies on wet AMD and DR have led to the development of anti-VEGF strategy for treating blood-retina barrier (BRB) breakdown in these diseases. To investigate the functional significance of VEGF signaling in major retinal supporting cells, Müller glia, we disrupted VEGF receptor-2 (VEGFR2) in mice and observed a significant loss of Müller cells, accelerated retinal neuron degeneration, and a substantial reduction of two neurotrophins: brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) in the retina in diabetes/hypoxia. In this study, we will determine the mechanism of VEGF signaling-mediated Müller cell viability, evaluate the significance of VEGF signaling in the production of neurotrophins, and explore therapeutic potential of supplying neurotrophins for neuroprotection in diabetic or hypoxic animals. Our study will contribute to the basis for establishing a general strategy to treat neuronal pathology in DR and other hypoxic retinal diseases and provide mechanistic insights for Müller glia as a cellular source of neuro-protectants in these diseases.

血管内皮生长因子（VEGF）是湿性年龄相关性疾病的主要致病因素 黄斑变性 (AMD) 和糖尿病视网膜病变 (DR) 是导致失明的主要原因 我们。对湿性 AMD 和 DR 的深入研究导致了抗 VEGF 策略的发展 治疗这些疾病中的血视网膜屏障（BRB）破坏。为了研究功能性 VEGF 信号传导在主要视网膜支持细胞、Müller 胶质细胞中的重要性，我们破坏了 VEGF 受体 2 (VEGFR2) 小鼠体内，观察到 Müller 细胞显着损失，视网膜加速 神经元变性，以及两种神经营养素的大量减少：脑源性 视网膜中的神经营养因子（BDNF）和神经胶质细胞源性神经营养因子（GDNF） 糖尿病/缺氧。在本研究中，我们将确定 VEGF 信号介导的机制 Müller 细胞活力，评估 VEGF 信号传导在神经营养素产生中的重要性， 并探索提供神经营养素对糖尿病或糖尿病患者神经保护的治疗潜力 缺氧动物。我们的研究将为制定治疗总体策略奠定基础 DR 和其他缺氧性视网膜疾病的神经元病理学，并提供机制见解 穆勒胶质细胞是这些疾病中神经保护剂的细胞来源。