Immune modulation and CNS pathology following exogenous ?-synuclein challenge

外源性 α-突触核蛋白攻击后的免疫调节和 CNS 病理学

• 批准号: 9388125
• 负责人: PARAMITA CHAKRABARTY
• 金额: $ 22.59万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9388125
• 关键词: Adaptive Immune System; Amyloid; Antigen Presentation; Antigens; Appearance; Attenuated; Bolus Infusion; Brain; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cells; Cellular Immunity; Characteristics; Chronic; Communication; Complex; Data; Disease; Epigenetic Process; Epitopes; Etiology; Exocytosis; Flow Cytometry; Freund' s Adjuvant; Future; Gastritis; Genes; Goals; Hindlimb; Human; Immune; Immune Sera; Immune response; Immune signaling; Immune system; Immunity; Immunodeficient Mouse; Immunotherapy; Infection; Inflammatory; Injectable; Injection of therapeutic agent; Intraperitoneal Injections; Knockout Mice; Laboratories; Lead; Length; Lewy Body Dementia; Lewy Body Disease; Light; Lymphoid; Mature B-Lymphocyte; Mediating; Mus; Mutation; Myeloid Cells; Nature; Nervous System Heredodegenerative Disorders; Nervous system structure; Neurodegenerative Disorders; Neuroimmune; Neurons; Oligodendroglia; Organ; Outcome; Outcome Measure; Paralysed; Parkinson Disease; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Peripheral; Peripheral Nervous System; Play; Preventive; Property; Proteins; Rag1 Mouse; Regulation; Reporting; Research Personnel; Rodent Model; Role; Seeds; Spinal Cord; Spinal Injections; Study models; Substantia nigra structure; Synaptic Vesicles; T-Lymphocyte; Testing; Time; Transgenic Mice; Transgenic Organisms; alpha synuclein; base; experience; experimental study; feeding; histological studies; immune activation; immunogenic; immunoregulation; influenzavirus; insight; mouse model; nano-string; neurodegenerative dementia; neuron loss; neurotoxicity; novel; preconditioning; prion-like; proteostasis; synuclein; synucleinopathy; transmission process; white matter

Progressive accumulation of intracellular inclusions of α-synuclein protein in the nervous system is a characteristic feature of Lewy Body diseases which is part of a spectrum of sporadic and hereditary neurodegenerative diseases termed α- synucleinopathies. The definitive involvement of α-synuclein in the etiology of these disorders was established by the findings that mutations in α-synuclein can directly cause Lewy body dementia. Many studies suggest that the progressive spread of α-synuclein pathology in the peripheral nervous system and the brain occurs through direct α-synuclein transmission between cells. However, there is a major gap in our understanding of the epigenetic factors that modulate such prionoid properties of α-synuclein. Our preliminary data suggests that α-synuclein is an immunogenic protein and that additional factors, such as activation of cellular immunity, may contribute to the prionoid propagation of peripherally administered exogenous α-synuclein to the CNS of mice. To provide novel insights into immune-mediated mechanisms involved in induction of CNS α-synuclein inclusion pathology following peripheral challenge with exogenous α-synuclein, we have assembled a team of experienced investigators with diverse and unique expertise in α-synuclein proteostasis and neuroimmune regulation. In Aim 1, we will determine whether inflammatory preconditioning of peripheral immune milieu exacerbates induction and CNS transmission of α-synuclein pathology following peripheral challenge with exogenous α- synuclein fibrils. In Aim 2, we will test whether the prionoid properties of α-synuclein fibrils is suppressed in two independent lines of immunodeficient α-synuclein transgenic mice. Our study will inform us on the interplay between α- synuclein seeding and propagation and cellular immunity. We expect our study to be highly translational as it will clarify 1) potential interactions between α-synuclein and cellular immunity and further help us 2) devise preventive immunobiotherapies strategies to slow down intercellular α-synuclein pathogenesis in the future.

神经系统中α-突触核蛋白蛋白的细胞内夹杂物的逐渐积累是一种特征 路易体疾病是一系列零星和遗传神经退行性疾病的一部分 综合病。 α-突触核蛋白在这些疾病的病因中的确切参与是由 发现α-突触核蛋白中的突变会直接引起Lewy身体痴呆。许多研究表明渐进式 α-突触核蛋白病理在周围神经系统中的传播和大脑通过直接α-核蛋白发生 细胞之间的传播。但是，我们对调节这种表观遗传因素的理解存在一个主要差距 α-突触核蛋白的phion型特性。我们的初步数据表明α-突触核蛋白是一种免疫原性蛋白，并且 其他因素，例如细胞免疫的激活，可能有助于外周的pro繁殖 对小鼠中枢神经系统的外源α-突触核蛋白施用。为免疫介导的机制提供新的见解 涉及在外周攻击后与外源性α-突触核蛋白，诱导CNSα-突触核蛋白纳入病理学， 我们组建了一支经验丰富的研究人员团队，在α-核蛋白蛋白质癌和 神经免疫调节。在AIM 1中，我们将确定外周免疫环境的炎症预处理是否 在外周挑战之后，外源性α-加剧α-突触核蛋白病理的诱导和中枢神经系统的传播 综合蛋白原纤维。在AIM 2中，我们将测试α-突触核蛋白原纤维的prionoid性能是否在两个中被抑制 免疫缺陷α-突触核蛋白转基因小鼠的独立线。我们的研究将告知我们α-之间的相互作用 综合蛋白的播种，传播和细胞免疫。我们预计我们的研究将被高度翻译，因为它将澄清 1）α-突触核蛋白和细胞免疫学之间的潜在相互作用并进一步帮助我们2）设计预防 未来减慢细胞间α-突触核蛋白发病机理的免疫疗法策略。