The Alternative Complement System Facilitates Photoreceptor Degeneration in Retinal Detachment.

替代补体系统促进视网膜脱离中的感光器变性。

基本信息

批准号：
9915924
负责人：
Kip M Connor
金额：
$ 42.5万
依托单位：
MASSACHUSETTS EYE AND EAR INFIRMARY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-01 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9915924
关键词：
Adjuvant Affect Alternative Complement Pathway Animal Model Animals Apoptosis Binding Blindness C3AR1 gene C5AR2 gene Cell Death Cells Cessation of life Complement Complement 3a Complement 5a Complement Inactivators Complement Receptor Complex Custom Data Degenerative Disorder Deposition Disease Disease Progression Ensure Event Excision Exhibits Eye Gene Chips Health Hour Human Hypoxia Immune Immunity Immunohistochemistry Immunologic Surveillance In Situ Hybridization Individual Inflammation Inflammation Mediators Inflammatory Injury Innate Immune System Interphase Cell Lasers Ligands Light Mediating Membrane Messenger RNA Microglia Modeling Molecular Molecular Profiling Mus Necrosis Nerve Degeneration Operative Surgical Procedures Oxygen Pathogenesis Pathologic Pathway interactions Patients Phagocytes Phagocytosis Photoreceptors Process Production Reagent Receptor Signaling Regulation Retina Retinal Detachment Role Sampling Sodium Hyaluronate Specificity Stress Structure of retinal pigment epithelium Surface System Therapeutic Agents Time Tissues Up-Regulation Vision Visual Visual Acuity Visual impairment Western Blotting cell type complement system cytokine genetic manipulation genetic regulatory protein in vivo interest macrophage mouse model nano-string neuroinflammation novel photoreceptor degeneration physical separation primary outcome receptor recruit repaired response response to injury retinal damage subretinal injection therapeutic target treatment strategy

项目摘要

Project Summary Retinal detachment (RD) and subsequent neurodegeneration of the retina continues to be a leading cause of visual impairment. In patients with sustained RD, progressive visual decline due to photoreceptor cell death is common and leads to a significant decrease in visual acuity. Numerous pathological changes occur in the detached retina and studies in human patient samples and in animal models have shown rapid photoreceptor cell death in response to RD. However, the underlying processes that facilitate this death have remained elusive and currently no treatments exist, aside from surgery to reattach the retina. Early inflammatory mediators are up-regulated in the eyes of patients with RD; of particular interest are those of the complement system. The complement system is an intricate immune surveillance system that is able to discriminate between healthy and diseased host tissue, and modulates the elimination and repair of host tissue accordingly. Within the ocular microenvironment, the alternative complement cascade exhibits low levels of constitutive activation and is tightly controlled by intraocular complement regulatory proteins. We have recently found that the alternative complement pathway is a vital regulator of photoreceptor cell death in response to injury. However, little is known about how this pathway becomes activated in RD. Interestingly, the complement receptors are potent downstream mediators of inflammation leading to the recruitment of immune cells and up- regulation of both complement proteins as well as pro-inflammatory cytokines from the local microenvironment Our preliminary data strongly implicates the complement receptors in photoreceptor cell death. To this end we hypothesize that the complement receptors, and their respective ligands, help facilitate a response against the stressed photoreceptors in the damaged retina, specifically targeting these cells for removal and increasing the inflammatory potential in the retinal microenvironment exacerbating this degenerative disease. We will utilize a well-defined mouse model of RD, in which a subretinal injection of sodium hyaluronate is used to create a detachment. The mouse RD model will allow us to take advantage of well-established genetic manipulation platforms in mice in a controlled setting. In order to characterize the role of the innate immune system in photoreceptor cell death we will: 1) Determine the role of complement receptors in mediating photoreceptor cell death in RD (Aim I); 2) Identify the regulatory mechanisms of complement production in response to RD (Aim II) and 3) To define the role of the complement receptors and microglia in RD disease pathogenesis (Aim III). It is our hope that this proposal will allow us to further characterize the role of the complement system in photoreceptor loss during RD, leading to therapies that protect individuals with RD as an adjuvant therapeutic agent to retinal detachment surgery.

项目摘要视网膜脱离（RD）和随后的视网膜神经变性仍然是视觉障碍。在持续RD的患者中，由于感光细胞死亡而导致的视觉下降是常见并导致视力显着下降。发生了许多病理变化脱离视网膜和人类患者样品和动物模型中的研究显示了快速感光体响应RD的细胞死亡。但是，促进死亡的基本过程仍然存在除了手术还可以重新融入视网膜外，难以捉摸且目前没有治疗。早期炎症 RD患者眼中的介体被上调。特别感兴趣的是补充的系统。补体系统是一种复杂的免疫监视系统，能够区分在健康和患病的宿主组织之间，并相应地调节宿主组织的消除和修复。在眼微环境中，替代补体级联反应表现出低水平的本构级激活，并由眼内补体调节蛋白紧密控制。我们最近发现替代补体途径是响应损伤的感光细胞死亡的重要调节剂。但是，关于该路径如何在RD中激活的知之甚少。有趣的是，补充受体是炎症的有效下游介体，导致免疫细胞和上升调节局部微环境的补体蛋白质以及促炎细胞因子我们的初步数据强烈暗示感光细胞死亡中的补体受体。为此，我们假设补体受体及其各自的配体有助于促进反应受损的视网膜中的压力感受器，特别针对这些细胞去除并增加视网膜微环境中的炎症潜力加剧了这种退化性疾病。我们将利用一个 RD定义明确的小鼠模型，其中使用透明钠钠的视网膜下注射来创建一个分离。鼠标RD模型将使我们能够利用建立的遗传操作在受控设置中，小鼠中的平台。为了表征先天免疫系统在感光细胞死亡我们将：1）确定补体受体在介导光感受器细胞中的作用 RD死亡（AIM I）； 2）确定响应RD的补体生产的调节机制（AIM ii）和3）定义补体受体和小胶质细胞在RD疾病发病机理中的作用（AIM III）。它我们希望该提议能够使我们能够进一步描述补体系统在 RD期间的感光受体损失，导致疗法可保护RD作为辅助治疗的人视网膜脱离手术的代理。