Targeting Innate Immunity as A Therapeutic Intervention for Parkinsons Disease

针对先天免疫作为帕金森病的治疗干预措施

• 批准号: 10356058
• 负责人: John David Beckham
• 金额: --
• 依托单位: VA EASTERN COLORADO HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10356058
• 关键词: Acute; Antibodies; Award; Biological Response Modifiers; Brain; Brain region; Clustered Regularly Interspaced Short Palindromic Repeats; Cytotoxic T-Lymphocytes; Data; Disease; Foundations; Gene Expression; Genes; Growth; Human; IFNAR1 gene; Immune; Immune System Diseases; Immune response; Immune signaling; Immunization; Immunologic Receptors; Inflammatory Response; Injury; Innate Immune Response; Interferon Receptor; Interferon Type I; Interferons; Knock-out; Knockout Mice; Laboratories; Measures; Mediating; Mediator of activation protein; Midbrain structure; Modeling; Monoclonal Antibodies; Mus; Natural Immunity; Nerve Degeneration; Neuraxis; Neurons; Neuropathogenesis; Outcome; Parkinson Disease; Pathogenesis; Pathology; Patients; Phase; Poly I-C; Proteins; RNA; Receptor Inhibition; Role; Signal Pathway; Signaling Molecule; Stimulant; T cell response; Therapeutic Intervention; Time; Virus; Virus Diseases; West Nile virus; Wild Type Mouse; Work; alpha synuclein; brain tissue; experimental study; innate immune pathways; innate immune sensing; insight; knockout gene; mouse model; neuroinflammation; neuron loss; neuropathology; nonhuman primate; novel; olfactory bulb; progressive neurodegeneration; prospective; response; screening; therapeutic target; type II interferon receptor

This proposal is a renewal of our current VA Merit award and is focused on understanding the interactions between innate immune responses and Parkinson’s Disease (PD) pathogenesis. We previously discovered that the neuronal protein, alpha-synuclein (α-syn), protects the brain from viral infections. With our current VA Merit support, we extended these findings to discover that α-syn expression in neurons is required for expression of neuronal interferon stimulated gene (ISG) expression independent of microglial activation during acute viral infection in the brain. Loss of neuron-specific expression of α-syn results in increased virus growth in primary human neurons and decreased activation of infiltrating cytotoxic T-cell responses. We extended these findings to show that stimulation of specific RNA sensing and signaling pathways within neurons activates ISGs in an α-syn-dependent mechanism. Our current mechanistic studies form the foundation for the current proposal. For the next phase of our work and the subject of the current VA merit award application, we want to understand the role of α-syn-dependent innate immune responses in progression of PD neuropathology. Our fundamental hypothesis is that PD is an innate immune disorder and that inhibition of specific innate immune pathways associated with α-syn-dependent innate immune responses will inhibit the progression of PD pathology. The Brundin laboratory, our collaborator, has developed a murine model of prodromal PD that recapitulates the spread of α-syn pathology from the olfactory bulb to the midbrain in mice. This proposal combines this disease relevant model with approaches for targeted knockout or stimulation of specific innate immune responses to determine the effect on propagation of α-syn pathology, neurodegeneration, and inflammatory responses in the brain. The three independent, related aims will provide novel insight into a potential disease-modifying therapeutic intervention for PD. The first aim will use target gene knockout of specific innate immune genes to determine the role of specific innate immune pathways on the progression of PD pathology. The second aim will use targeted stimulation of select innate immune pathways and evaluate the effect on PD pathology. The third aim will employ inhibitory antibodies for specific innate immune pathways and determine the role of antibody-mediated inhibition of selected innate immune pathways on the progression of PD pathology. If the studies are completed as outlined, we will identify potential disease modifying targets for the treatment of PD.

该提议是我们当前VA功绩奖的续签，并专注于理解互动 在先天免疫反应与帕金森氏病（PD）发病机理之间。我们以前发现了 神经元蛋白Alpha-核蛋白（α-Syn）可保护大脑免受病毒感染的影响。与我们目前的VA 优点支持，我们扩展了这些发现，以发现神经元中的α-Syn表达需要 神经元干扰的表达刺激基因（ISG）表达与小胶质细胞激活无关。 大脑中的急性病毒感染。神经特异性表达α-Syn的表达导致病毒生长增加 在原发性人神经元中，改善了浸润细胞毒性T细胞反应的激活。我们扩展了 这些发现表明了神经元内特定RNA敏感性和信号通路的刺激 在α-Syn依赖性机制中激活ISG。我们当前的机械研究构成了 当前的建议。 对于我们的下一阶段和当前VA优异奖申请的主题，我们希望 了解α-Syn依赖性的先天免疫回报在PD神经病理发展中的作用。我们的 基本假设是PD是先天性免疫剂，并且抑制特定的先天免疫 与α-Syn依赖性的先天免疫回报相关的途径将抑制PD的进展 病理。 我们的合作者Brundin实验室已经开发了一种鼠模型的前驱PD模型 概括了小鼠α-Syn病理学从嗅球到中脑的扩散。这个建议 将这种疾病友好的模型与针对性敲除或刺激特定先天的方法相结合 免疫反应以确定对α-Syn病理学，神经退行性和神经退行性和 大脑的炎症反应。这三个独立的相关目标将为您提供新颖的见解 PD的潜在调整治疗干预措施。 第一个目标将使用特定先天免疫基因的目标基因敲除确定的作用 PD病理进展的特定先天免疫途径。第二个目标将使用目标 刺激精选先天免疫途径并评估对PD病理的影响。第三个目标 对特定先天免疫途径的员工抑制抗体，并确定抗体介导的作用 抑制选定的先天免疫途径对PD病理进展的抑制。如果研究是 按照概述完成，我们将确定可修改PD治疗靶标的潜在疾病。