Innate and Adaptive Immunity in Parkinson Disease

帕金森病的先天性和适应性免疫

• 批准号: 10253371
• 负责人: DAVID G. STANDAERT
• 金额: $ 0.15万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-07 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10253371
• 关键词: Address; Alabama; Animal Disease Models; Animal Model; Autopsy; Award; Bone Marrow Transplantation; Cells; Clinical; Communities; Development; Disease; Disease model; Education and Outreach; Environment; Future; Grant; Human; Immune; Immune Targeting; Immune response; Immune system; Immunoglobulins; Innate Immune System; LRRK2 gene; Ligands; Link; Mission; Modeling; National Institute of Neurological Disorders and Stroke; Natural Immunity; Nature; Nerve Degeneration; Parkinson Disease; Pathogenesis; Patients; Persons; Physicians; Production; Reporting; Research; Research Personnel; Role; Sampling; Scientist; Signal Pathway; Signal Transduction; Substantia nigra structure; Symptoms; T-Lymphocyte; Testing; Training; Tumor-infiltrating immune cells; Work; adaptive immune response; adaptive immunity; alpha synuclein; brain tissue; chemokine; cytokine; genetic approach; human subject; immune activation; inhibitor/antagonist; innovation; monocyte; mouse synuclein alpha; neuroinflammation; neuroprotection; next generation; perineural; preclinical study; prevent; programs; response; small molecule; targeted treatment; therapy development

Alabama Udall Center: Overall The development of neuroprotective strategies for 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 Program Project 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, in order to accelerate progress towards the 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.

阿拉巴马州尤德尔中心：整体 开发帕金森病的神经保护策略是一个重要的未得到满足的需求。正如提交给委员会的报告所述 NINDS Council(PD2014)，“关注帕金森病的调查人员社区现在努力创造出 有意义地延缓或停止帕金森氏症所有症状背后的疾病机制。阿拉巴马州的Udall 中心是对这些需求的响应，也是我们在NINDS探索性资助计划下工作的产物 帕金森氏病研究(P20NS092530)。 长期以来，人们一直认为帕金森病死后的脑组织中存在先天的激活 免疫系统，黑质明显的小胶质细胞增多症，并增加了 细胞因子和趋化因子。最近，很明显，也有适应性免疫的激活， 神经周围有T细胞浸润和免疫球蛋白积聚。我们设想一个更好的 了解帕金森病的免疫变化将确定特定的靶点和治疗策略 神经退行性变。 该方案项目将涉及两个总体科学目标：1)确定 以及2)确定是否抑制LRRK2和JAK/STAT信号转导 这些通路可以阻止与α-突触核蛋白相关的神经退行性变背后的免疫反应。我们的中央 假设先天和获得性免疫细胞，特别是单核细胞和T细胞在早期被激活。 阻断这些细胞中的LRRK2或JAK/STAT信号将防止神经退化。 我们将利用先进的小分子配体和抑制剂，遗传方法，亚集的详细研究 免疫细胞和骨髓移植方法来验证这一假设。每个项目都是固定的 通过临床核心将提供来自人类受试者的样本，动物模型核心将提供 协调阿尔法突触核蛋白小鼠帕金森病原纤维模型的临床前研究。 阿拉巴马州乌德尔中心还有与培训和外联有关的重要任务。我们寻求训练 下一代科学家和医生，为了加快帕金森病治疗的进展 以及未来的治疗方法。我们将与帕金森病患者社区合作，他们是我们的合作伙伴 努力。我们寻求创造一个专注于识别先天免疫和获得性免疫的团队和环境 应对帕金森病发病机制的关键，并迅速推进创新，跨学科，影响极大 研究计划。