Innate and Adaptive Immunity in Parkinson Disease

帕金森病的先天性和适应性免疫

• 批准号: 9788111
• 负责人: DAVID G. STANDAERT
• 金额: $ 193.19万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9788111
• 关键词: Address; Alabama; Animal Disease Models; Animal Model; Attenuated; Autopsy; Award; B-Lymphocytes; Biological Models; Blood; Bone Marrow; Bone Marrow Transplantation; Brain; Brain Diseases; CD8-Positive T-Lymphocytes; Cells; Cerebrospinal Fluid; Clinical; Cognition; Collaborations; Communities; Cross-Sectional Studies; Data; Development; Disease; Disease model; Disease susceptibility; Education and Outreach; Elements; Encephalitis; Environment; Functional disorder; Future; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic study; Genome; Goals; Grant; HLA-DR Antigens; Human; Hyperactive behavior; Imaging ligands; Immune; Immune Targeting; Immune response; Immune system; Immunoglobulins; Inflammatory; Inflammatory Response; Innate Immune System; Interferons; LRRK2 gene; Ligands; Link; Lymphoid Cell; Measures; Mediating; Microglia; Mission; Modeling; Mutation; Myelogenous; National Institute of Neurological Disorders and Stroke; Natural Immunity; Nature; Nerve Degeneration; Outcome; Parkinson Disease; Pathogenesis; Pathology; Pathway Analysis; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Physicians; Population; Positron-Emission Tomography; Production; Property; Publications; Recommendation; Reporting; Research; Research Personnel; Rodent Model; Role; Sampling; Scientist; Signal Pathway; Signal Transduction; Structure; Substantia nigra structure; Symptoms; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Tissues; Toxic effect; Training; Tumor-infiltrating immune cells; Variant; Work; Yolk Sac; adaptive immune response; adaptive immunity; alpha synuclein; base; brain tissue; chemokine; clinical predictors; cohort; cytokine; genetic approach; genome analysis; human subject; imaging study; immune activation; immune function; inhibitor/antagonist; innovation; macrophage; member; monocyte; mouse synuclein alpha; neuroinflammation; neuroprotection; next generation; novel; perineural; preclinical study; prevent; programs; recruit; response; small molecule; symposium; synergism; targeted treatment; therapy development

The development of neuroprotective strategies for Parkinson’s disease (PD) is a vital unmet need. As stated in the Report to the NINDS Council (PD2014), “the community of investigators focused on PD now strives to create therapies that meaningfully slow or stop the disease mechanisms that underlie all symptoms of PD”. The Alabama Udall Center is a response to these needs, and a product of our work under an NINDS Exploratory Grant Program in Parkinson's Disease Research (P20NS092530). It has long been recognized that in post-mortem brain tissue from PD there is activation of the innate immune system, with prominent microgliosis in the substantia nigra together with enhanced production of cytokines and chemokines. Recently, it has become clear that there is also activation of adaptive immunity, with infiltration of T-cells and accumulation of immunoglobulins in perineural regions. We envisage that a better understanding of immune changes in PD will identify specific targets and therapeutic strategies that will block neurodegeneration. This Center will address two overall scientific Aims: 1) to determine the extent and nature of immune activation in early human PD; and 2) to determine whether inhibiting LRRK2 and JAK/STAT signaling pathways can block immune responses that underlie alpha-synuclein linked neurodegeneration. Our central hypothesis is that innate and adaptive immune cells, particularly monocytes and T-cells, are activated early in disease, and that blocking LRRK2 or JAK/STAT signaling in these cells will protect from neurodegeneration. We will utilize advanced small molecule ligands and inhibitors, genetic approaches, detailed studies of subsets of immune cells and bone marrow transplantation approaches to test the hypothesis. Each project is anchored through the Clinical Core that will provide samples from human subjects, and the Animal Models Core that harmonizes pre-clinical studies in the alpha-synuclein mouse fibril model of PD. The Alabama Udall Center also has important missions related to training and outreach. We seek to train the next generation of scientists and physicians, to accelerate progress towards PD treatments and cures of the future. We will engage the community of persons with PD who are our partners in these efforts. We seek to create a team and environment focused on the identification of innate and adaptive immune responses critical to PD pathogenesis, and rapidly advance an innovative, interdisciplinary, highly impactful research program.

帕金森病 (PD) 的神经保护策略的开发是一项尚未得到满足的重要需求。正如向 NINDS 理事会提交的报告 (PD2014) 中所述，“专注于 PD 的研究人员群体现在正在努力开发能够有效减缓或阻止 PD 所有症状背后的疾病机制的疗法”。阿拉巴马州尤德尔中心是对这些需求的回应，也是我们在 NINDS 帕金森病研究探索性资助计划 (P20NS092530) 下工作的产物。 人们早已认识到，在帕金森病死后脑组织中，先天免疫系统被激活，黑质中出现显着的小胶质细胞增生，同时细胞因子和趋化因子的产生增强。最近，人们已经清楚，随着 T 细胞的浸润和神经周围区域免疫球蛋白的积累，适应性免疫也被激活。我们预计，更好地了解帕金森病的免疫变化将确定阻止神经退行性变的特定靶点和治疗策略。 该中心将实现两个总体科学目标：1）确定早期人类帕金森病免疫激活的程度和性质； 2) 确定抑制 LRRK2 和 JAK/STAT 信号通路是否可以阻断与 α-突触核蛋白相关的神经变性背后的免疫反应。我们的中心假设是，先天性和适应性免疫细胞，特别是单核细胞和 T 细胞，在疾病早期被激活，阻断这些细胞中的 LRRK2 或 JAK/STAT 信号传导将防止神经退行性变。我们将利用先进的小分子配体和抑制剂、遗传方法、免疫细​​胞亚群的详细研究和骨髓移植方法来检验这一假设。每个项目都以提供人类受试者样本的临床核心和协调 PD α-突触核蛋白小鼠原纤维模型的临床前研究的动物模型核心为基础。 阿拉巴马州尤德尔中心还担负着与培训和外展相关的重要使命。我们寻求培训下一代科学家和医生，以加快未来帕金森病治疗和治愈的进展。我们将让作为我们合作伙伴的帕金森病患者社区参与这些努力。我们寻求创建一个团队和环境，专注于识别对帕金森病发病机制至关重要的先天性和适应性免疫反应，并迅速推进创新、跨学科、极具影响力的研究计划。