Microglial Activation during Photoreceptor Degeneration

光感受器变性期间的小胶质细胞激活

• 批准号: 10394346
• 负责人: MARIE E BURNS
• 金额: $ 47.1万
• 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 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10394346
• 关键词: ARRB1 gene; Apoptosis; Biochemical; Blindness; Cell Proliferation; Cells; Cellular Stress; Destinations; Disease; Early Diagnosis; Evolution; Flow Cytometry; Gene Expression; Genetic; Goals; Heterogeneity; Homeostasis; Hour; Image; Immune; Immune response; Immunohistochemistry; In Situ Hybridization; Individual; Inflammatory; Invaded; Investigational Therapies; Ion Channel; Label; Lasers; Light; Longevity; Membrane; Methodology; Methods; Microglia; Modeling; Molecular; Molecular Profiling; Monitor; Nature; Nerve Degeneration; Neuronal Injury; Neurons; Phagocytosis; Phase; Phenotype; Photoreceptors; Physiologic pulse; Play; Population; Population Heterogeneity; Process; Property; Proteins; Recovery; Research; Resolution; Retina; Retinal Degeneration; Role; Schedule; Signal Transduction; Stress; Supporting Cell; Symptoms; Techniques; Testing; Time; Tissues; Validation; Visual impairment; Work; adaptive optics scanning laser ophthalmoscopy; cell behavior; cell motility; cell type; extracellular; gene replacement therapy; human disease; imaging approach; immune activation; improved; in vivo; in vivo imaging; macrophage; molecular imaging; monocyte; neurotrophic factor; photoreceptor degeneration; prevent; programs; protein expression; receptor; recruit; response; retina blood vessel structure; retinal imaging; single-cell RNA sequencing; stem-like cell; tissue repair

Project Summary Retinal degeneration is a leading cause of blindness worldwide. 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 degeneration is activation of an immune response, as the resident macrophages, called microglia, and infiltrating monocytes migrate to and phagocytose injured neurons. The proposed research will utilize high- resolution, in vivo OCT and AO-SLO imaging, flow cytometry, scRNAseq and biochemical and immunohistochemical approaches to study the microglial response to photoreceptor degeneration (Aim 1), the fates of infiltrating monocytes (Aim 2), and the involvement of both cell types in re-establishing new homeostasis after dying photoreceptors have been cleared (Aim 3). This work will contribute to the long-term goal of monitoring and manipulating microglial dynamics in vivo so as to provide earlier detection of and assessment of treatments for retinal degenerative disease.

项目摘要 视网膜变性是世界范围内失明的主要原因。所有当前治疗 包括干细胞或基因等实验性治疗方法 替代疗法，被认为是最有效的，当变性是陷入其 最早的阶段不幸的是，最早可检测到的退化症状往往是 视力受损，只有在大量视网膜细胞死亡后才能检测到 然后消失了在细胞凋亡之前辨别细胞应激的最初迹象的能力 和退化，可以显着提高延迟或预防 视力丧失退化的一个常见早期迹象是免疫系统的激活。 反应，如驻留的巨噬细胞（称为小胶质细胞）和浸润的单核细胞 迁移并吞噬受损的神经元。该研究将利用高- 分辨率、体内OCT和AO-SLO成像、流式细胞术、scRNAseq和 生物化学和免疫组织化学方法来研究小胶质细胞对 光感受器变性（Aim 1），浸润单核细胞的命运（Aim 2），以及 死亡后两种细胞类型参与重建新的稳态 光感受器已被清除（目标3）。这项工作将有助于长期 目的是在体内监测和操纵小胶质细胞动力学，以便更早地提供 检测和评估视网膜变性疾病的治疗。