Microglial Activation during Photoreceptor Degeneration

光感受器变性期间的小胶质细胞激活

• 批准号: 9130216
• 负责人: MARIE E BURNS
• 金额: $ 47.34万
• 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 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9130216
• 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; Gene Expression; Goals; Health; Image; Immune; Immune response; Individual; Infiltration; Inflammation; Investigational Therapies; Label; Lasers; Lead; Light; Methods; Microglia; Modeling; Monitor; Morphology; Mus; Neurons; Normal Statistical Distribution; Nuclear; Ophthalmoscopy; Optical Coherence Tomography; Phagocytosis; Photoreceptors; Phototransduction; Physiological; Productivity; Proliferating; Purines; Recruitment Activity; Resolution; Retina; Retinal; Retinal Degeneration; Role; Scanning; Signal Transduction; Societies; Specific qualifier value; Staging; Stem cells; Stereotyping; Stratification; Stress; Surface; Symptoms; Systemic disease; Testing; Time; Tissues; Transducin; Viral Vector; Visual impairment; Work; adaptive optics; cell type; chemokine; cost; disability; extracellular; gene replacement therapy; imaging modality; improved; in vivo; injured; macrophage; migration; molecular marker; monocyte; neuronal cell body; optical imaging; photoreceptor degeneration; prevent; research study; response; retinal rods; spatiotemporal; 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(申请人提供)：视网膜退化是导致失明的主要原因，每年给社会造成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，这一负担将进一步恶化。目前治疗视网膜变性的所有疗法，包括干细胞或基因替代疗法等实验性疗法，都被认为在变性发生的最早阶段最有效。不幸的是，退化最早可检测到的症状往往是视力受损，只有在大量视网膜细胞死亡和消失后才能检测到。在细胞凋亡和退化之前识别细胞应激的第一个迹象的能力，可以显著提高延缓或防止视力丧失的可能性。即将发生变性的一个常见早期迹象是视网膜小胶质细胞的激活，小胶质细胞是常驻的视网膜免疫细胞，可以增殖、迁移到受损的神经元并吞噬受损的神经元。这项拟议的工作将确定光感受器退化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，我们将在体内确定个体视网膜小胶质细胞的三维形态和动力学，包括健康组织和光感受器应激和退化的最早阶段(目标1)。我们还将确定触发小胶质细胞迁移到视网膜外部的信号，并指定光感受器吞噬(目标2)。最后，我们将确定循环中的巨噬细胞渗入外视网膜的时间进程，并评估这两种细胞促进或破坏光感受器存活的程度(目标3)。这项工作将有助于实现监测和操纵体内小胶质细胞动力学的长期目标，从而为视网膜退行性疾病的早期检测和治疗提供评估。