Microglial Activation during Photoreceptor Degeneration

光感受器变性期间的小胶质细胞激活

• 批准号: 9546733
• 负责人: MARIE E BURNS
• 金额: $ 45.46万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9546733
• 关键词: 3-Dimensional; ARRB1 gene; Age; Aging; Animal Model; Apoptosis; Arrestins; Blindness; Blood-Retinal Barrier; CCL2 gene; Cells; Cellular Stress; Chemotactic Factors; Confocal Microscopy; Coupling; Cues; Dimensions; Early Diagnosis; GTP-Binding Proteins; Gap Junctions; Gene Expression; Goals; Image; Immune; Immune response; Individual; Infiltration; Inflammation; Investigational Therapies; Label; Lead; Light; Methods; Microglia; Modeling; Monitor; Morphology; Mus; Neurons; Normal Statistical Distribution; Nuclear; Optical Coherence Tomography; Phagocytes; Photoreceptors; Phototransduction; Physiological; Productivity; Proliferating; Purines; Quantitative Reverse Transcriptase PCR; Resolution; Retina; Retinal; Retinal Degeneration; Role; Signal Transduction; Societies; Specific qualifier value; Stereotyping; Stratification; Stress; Surface; Symptoms; Systemic disease; Testing; Thinness; Time; Tissues; Transducin; Viral Vector; Visual impairment; Work; adaptive optics; adaptive optics scanning laser ophthalmoscopy; baby boomer; cell type; chemokine; cost; disability; experimental study; extracellular; gene replacement therapy; imaging modality; improved; in vivo; in vivo evaluation; injured; macrophage; migration; molecular marker; monocyte; neuronal cell body; optical imaging; photoreceptor degeneration; prevent; public health relevance; recruit; response; retinal rods; spatiotemporal; stem-like cell; transcriptome sequencing; two-photon

 DESCRIPTION (provided by applicant): Retinal degeneration is the leading cause of blindness and costs society billions of dollars annually in disability and lost productivity, a burden that is predicted to worsen as baby-boomers age. All current treatments for retinal degeneration, including experimental therapeutics like stem cell or gene replacement therapy, are thought to be most effective when degeneration is caught in its earliest stages. Unfortunately, the earliest detectable symptom of degeneration is often visual impairment, which is only detectable after a large number of retinal cells have died and disappeared. The ability to discern the first signs of cell stress, prior to apoptosis and degeneration, could significantly improve the likelihood of delaying or preventing vision loss. One common early indication of pending degeneration is activation of retinal microglia, the resident retinal immune cells, which can proliferate, migrate to and phagocytose injured neurons. The proposed work will define the earliest changes in microglia during photoreceptor degeneration. Using high-resolution, adaptive optics imaging, we will determine the 3-dimensional morphology and dynamics of individual retinal microglia in vivo, both in healthy tissue and during the earliest stages of photoreceptor stress and degeneration (Aim 1). We will also determine the signals that trigger microglial migration to the outer retina and specify photoreceptor engulfment (Aim 2). Finally, we will determine the time course by which circulating macrophages infiltrate the outer retina, and evaluate the degree to which both of these cell types promote or undermine photoreceptor survival (Aim 3). This work will contribute to the long-term goal to monitor and manipulate microglial dynamics in vivo so as to provide earlier detection of and assessment of treatments for retinal degenerative disease.

 描述（由申请人提供）：视网膜变性是失明的主要原因，每年使社会损失数十亿美元的残疾和生产力损失，预计随着婴儿潮一代的年龄增长，这一负担将恶化。目前所有针对视网膜变性的治疗方法，包括干细胞或基因替代疗法等实验性治疗方法，都被认为在变性的最早阶段最有效。不幸的是，最早可检测到的退化症状通常是视力障碍，这只有在大量视网膜细胞死亡和消失后才能检测到。在细胞凋亡和变性之前识别细胞应激的第一个迹象的能力可以显着提高延迟或预防视力丧失的可能性。一种常见的即将发生变性的早期迹象是视网膜小胶质细胞的激活，视网膜小胶质细胞是常驻的视网膜免疫细胞，其可以增殖、迁移到并吞噬受损的神经元。拟议的工作将定义感光细胞变性过程中小胶质细胞的最早变化。使用高分辨率，自适应光学成像，我们将确定三维形态和动态的个体视网膜小胶质细胞在体内，无论是在健康的组织和感光细胞的应力和退化的最早阶段（目标1）。我们还将确定触发小胶质细胞迁移到视网膜外层的信号，并指定感光细胞吞噬（目标2）。最后，我们将确定循环巨噬细胞浸润外视网膜的时间进程，并评估这两种细胞类型促进或破坏感光细胞存活的程度（目的3）。这项工作将有助于长期目标，监测和操纵小胶质细胞的动态在体内，以便提供早期检测和评估视网膜退行性疾病的治疗。