Role of Microglia in Retinitis Pigementosa

小胶质细胞在色素性视网膜炎中的作用

• 批准号: 9899490
• 负责人: Oleg Butovsky
• 金额: $ 12.23万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9899490
• 关键词: Ablation; Address; Adult; Affect; Age of Onset; Alzheimer' s Disease; Animal Model; Animals; Antibodies; Apoptosis; Apoptotic; Applications Grants; Biology; Blindness; Brain; Cell Lineage; Cells; Characteristics; Chronic; Cone; DNA Sequence Alteration; Data; Development; Disease; Disease Progression; Eye; Genes; Genetic; Human; Individual; Infiltration; Inflammation; Inflammatory; Inherited; Innate Immune System; Lateral; Lead; Literature; MERTK gene; Maintenance; Mediating; Microglia; Modeling; Molecular; Molecular Profiling; Mus; Mutation; Myelogenous; Neonatal; Nerve Degeneration; Night Blindness; Normal tissue morphology; Opsin; Pathogenicity; Pathway interactions; Patients; Peripheral; Phagocytosis; Phenotype; Photoreceptors; Prevalence; Proliferating; Property; Reporting; Retina; Retinal; Retinal Cone; Retinal Degeneration; Retinitis; Retinitis Pigmentosa; Review Literature; Role; Signal Transduction; Spinal; Stress; Symptoms; TREM2 gene; Transforming Growth Factor beta; Vertebrate Photoreceptors; Vision; Visual Fields; Work; base; cytotoxic; cytotoxicity; effective therapy; emerging adult; genetic profiling; human subject; immunoregulation; inherited retinal degeneration; innovation; insight; macrophage; monocyte; mouse model; neuroinflammation; neurotoxic; new technology; new therapeutic target; novel; novel strategies; preservation; recruit; response; restoration; retinal damage; retinal rods; targeted treatment; therapeutic target; tool

PROJECT SUMMARY/ABSTRACT: Microglia are resident myeloid-lineage cells in both the CNS and in the eye and function in the maintenance of normal tissue. Retinal microglia can become activated and/or dysregulated during disease, and thus affect disease progression in retinitis pigmentosa. Understanding the biology of microglia is a challenge due to absence of markers and molecular microglia signatures. Recently, we identified a homeostatic molecular microglia signature which provides new tools for investigating retinal microglial biology and the possibility of targeting retinal microglia for the treatment of retinitis pigmentosa. Using our new microglial markers, we investigated microglia in the rd1 murine models of RP. We found increased numbers of resident microglia but no infiltration of monocytes in the retinal. Most importantly, we found that intravitreal transfer of microglia from animals with RP into normal animals, resulted in photoreceptor loss. Consistent with this, intravitreal transfer of retinal microglia from normal animals into animals with RP reduced photoreceptors loss. We hypothesize that in RP, microglia proliferate and acquire a cytotoxic phenotype mediated by intrinsic activation of the TREM2-APOE pathway which suppresses microglia homeostatic molecular properties and leads to uncontrolled chronic inflammation and photoreceptors damage. Treatments aimed to target microglia by suppressing the TREM2-APOE pathway is associated with activation of both the TGFβ pathway and MERTK which abrogates the inflammatory microglial phenotype and restores retinal microglial homeostatic properties. This provides a new direction for studying RP and development of novel therapies that target microglia. We believe that an innovative feature of our approach is that it is a mutation- independent approach that applies to RP independent of the genetic mutation. In addition, there is a translational aspect to the proposed work as we will investigate human eyes with our recently described microglial antibodies. We will address the following specific aims: Aim 1. Identify molecular pathways affected in retinal microglia in mouse models and human RP. Aim 2. Target the TREM2-APOE-SPP1 pathway to inhibit MGnD-cytotoxic microglia in rd mice. Aim 3. Restore M0-homeostatic microglia via TGFβ1-MERTK signaling in rd mice.

项目摘要/摘要：小胶质细胞是CNS和 维持正常组织的眼睛和功能。视网膜小胶质细胞可以激活和/或 疾病期间失调，因此影响色素性视网膜炎的疾病进展。了解 小胶质细胞的生物学是由于缺乏标记和分子小胶质细胞特征而挑战。最近，我们 确定了稳态的分子小胶质细胞签名，该签名提供了研究视网膜的新工具 小胶质细胞生物学以及靶向视网膜小胶质细胞来治疗视网膜炎色素的可能性。 使用新的小胶质细胞标记，我们研究了RP的RD1鼠模型中的小胶质细胞。我们发现 居民小胶质细胞的数量增加，但在其余部分没有单核细胞浸润。最重要的是，我们 发现玻璃体内转移的小胶质细胞从带有RP的动物转移到正常动物中，导致感光体 损失。与此相一致的是，玻璃体内小胶质细胞从正常动物转移到具有RP的动物 减少感光体损失。 我们假设在RP中，小胶质细胞增殖并获得由细胞毒性表型介导的 Trem2-APOE途径的固有激活，可抑制小胶质细胞稳态分子 性质和导致不受控制的慢性感染和感光体损害。治疗 旨在通过抑制trem2-apoe途径来靶向小胶质细胞 TGFβ途径和MERTK废除炎症小胶质表型并恢复残留 小胶质稳态特性。这为研究RP和新颖的发展提供了新的方向 靶向小胶质细胞的疗法。我们认为，我们方法的创新特征是它是一个突变 - 独立的方法适用于独立于遗传突变的RP。此外，还有一个 提议的工作的翻译方面，我们将用最近描述的人进行调查人眼 小胶质细胞抗体。我们将解决以下具体目标： AIM 1。确定小鼠模型和人RP中视网膜小胶质细胞影响的分子途径。 AIM 2。靶向TREM2-APOE-SPP1途径，以抑制RD小鼠中MGND-胞毒性小胶质细胞。 AIM 3。通过RD小鼠中的TGFβ1-MERTK信号来恢复M0骨层小胶质细胞。