Investigating the role of retinal astrocytes in exercise-induced retinal neuroprotection

研究视网膜星形胶质细胞在运动引起的视网膜神经保护中的作用

• 批准号: 10484539
• 负责人: Katie Leigh Bales
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10484539
• 关键词: Affect; Affinity; Age related macular degeneration; Animal Model; Astrocytes; Atrophic; Award; Biological Assay; Biology; Blindness; Blood Vessels; Brain; Brain-Derived Neurotrophic Factor; Cell Density; Cell Separation; Cells; Cellular Morphology; Clinical Research; Clinical Trials; Computer software; Data; Disease; Disease Progression; Endothelial Cells; Exercise; Exhibits; Foundations; Functional disorder; Future; Gene Expression; Goals; Healthcare; Hyperemia; Image; In Vitro; Inbred BALB C Mice; Inflammation; Intervention; Knowledge; Label; Light; Light Exercise; Magnetism; Mediating; Modeling; Modification; Molecular; Monitor; Morphology; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Plasticity; Neurotrophic Tyrosine Kinase Receptor Type 2; Outcome Study; Pathogenesis; Pathology; Patients; Persons; Phagocytosis; Pharmacology; Phenotype; Photoreceptors; Physiological; Process; Research; Retina; Retinal Degeneration; Retinitis Pigmentosa; Retrospective Studies; Role; Severities; Severity of illness; Signal Transduction; Stress; Structure; Testing; Therapeutic; Translating; Up-Regulation; Vascular Endothelial Cell; Veterans; Vision; Visual impairment; Writing; antagonist; base; cell type; density; exercise intervention; experimental group; gain of function; gene function; improved; improved functioning; military veteran; mouse model; neural repair; neuroinflammation; neuroprotection; neurovascular coupling; novel; patient population; preservation; receptor; relating to nervous system; repaired; response

Photoreceptor dysfunction is one of the hallmark pathologies associated with retinal degenerative (RD) diseases that manifests in patients as a progressive loss of vision. This encompasses heterogenous diseases such as retinitis pigmentosa, which affects 1 in 3500 people worldwide and age-related macular degeneration, which affects over 196 million people worldwide and is projected to reach 288 million people by 2040. Specifically, in our Veteran population, roughly 7,000 Veterans become visually impaired each year due to RD. Clinical trials and retrospective studies suggest that RD patients may respond to exercise as a neuroprotective treatment to preserve vision. Recently, our labs filled a significant knowledge gap by demonstrating that modest exercise protects retinal function and structure in models of RD and were accompanied by increased levels of brain derived neurotrophic factor (BDNF) and required intact BDNF-TrkB signal transduction. To date, the cell-types and molecular processes mediating the neuroprotective benefits of exercise are unknown. Others have shown that astrocytes and endothelial cells in the brain express BDNF and its high-affinity receptor, TrkB, and that altered BDNF-TrkB signaling in these cell-types contributes to neurodegenerative disease progression and severity. Recently, it has been demonstrated that astrocytes modify their morphology in response to BDNF in the brain during neurodegeneration. Likewise, vascular endothelial cells express BDNF under exercise-induced physiological stress. These data suggest that astrocytes and endothelial cells may mediate the neuroprotective effects of exercise in the retina. Our approach is to understand the morphological, gene expression and functional alterations in retinal astrocytes and vasculature induced from exercise and how these alterations contribute to neuroprotection. For this proposal, we will use the BALB/c light induced retinal degeneration model, which exhibits phenotypes found in patients with RD. We hypothesize that exercise induces retinal astrocyte plasticity and improved vascular function through increased BDNF signaling mechanisms, promoting neural repair and protection. In Specific Aim 1, we will investigate if exercise influences retinal astrocyte biology, by assessing retinal astrocyte morphology, cellular gene expression profiles, and retinal astrocyte-mediated phagocytosis. Immunohistochemical labeling, AnalyzeSkeleton and Sholl analysis will be used to quantify astrocyte cell morphology and density. Retinal astrocytes will be isolated using magnetic-activated cell sorting (MACS) to examine astrocyte gene expression profiles. To monitor retinal astrocyte function, a novel in vitro live-imaging of astrocyte-mediated phagocytosis will be used. In Specific Aim 2, we will determine the effects of exercise on retinal vascular morphology, gene expression and function. Angiotool will be used for retinal vascular morphology quantification analysis. Retinal vascular cell gene expression profiles will be assessed by MACS and vascular function will be assessed using retinal functional hyperemia. In Specific Aim 3, we will determine if exercise-induced BDNF signaling mechanisms influence retinal astrocyte and vascular morphology, gene expression and function, by blocking BDNF signaling using a highly specific TrkB receptor antagonist, ANA-12. Retinal astrocyte and vascular assessments performed in Specific Aims 1 and 2 found to be most informative will be used to compare experimental groups. The expected outcome of this study is that exercise-induced BDNF signaling alters retinal astrocyte and vascular morphology, gene expression and improves function in order to promote retinal neuroprotection. Results from this study will illuminate the morphological, gene expression and functional alterations that ultimately result in gain of function(s) and or loss/upregulation of homeostatic function(s) in retinal astrocytes and vasculature. This proposal holds profound potential for the long-term goals of optimizing exercise-based therapeutics and creating new pharmacological strategies targeting the underlying mechanisms of exercise-induced protection in patients with RD that can be extended to other neurodegenerative and neuroinflammatory diseases.

光感受器功能障碍是视网膜变性（RD）相关的标志性病理之一。