Innate and Adaptive Immunity in Parkinson Disease

帕金森病的先天性和适应性免疫

基本信息

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
项目类别：
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

项目摘要

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.

帕金森氏病神经保护策略（PD）的发展是至关重要的需求。正如向NINDS理事会（PD2014）的报告中所述，“关注PD的调查人员社区现在致力于创造有意义地减慢或阻止所有PD症状的疾病机制的疗法”。阿拉巴马州乌德尔中心（Alabama Udall Center）是对这些需求的回应，也是帕金森氏病研究（P20NS092530）的Ninds探索性赠款计划下的工作产物。长期以来，人们已经认识到，在PD的验尸后脑组织中，先天性免疫系统激活了，在Nigra中有明显的小胶质细胞增多，以及增强的细胞因子和趋化因子的产生。最近，很明显，自适应免疫组织化学也激活了T细胞的浸润和周围神经区域中免疫球蛋白的积累。我们设想，对PD的免疫变化有更好的了解将确定会阻止神经变性的特定靶标和治疗策略。该中心将解决两个总体科学目的：1）确定早期人类PD中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止α-突触核蛋白连接神经变性的免疫调查。我们的中心假设是，在疾病早期激活了先天和适应性免疫细胞，尤其是单核细胞和T细胞，并且在这些细胞中阻止LRRK2或JAK/Stat信号传导会保护神经变性。我们将利用晚期的小分子配体和抑制剂，遗传方法，对免疫细胞子集的详细研究以及骨髓移植方法检验该假设。每个项目都通过临床核心锚定，该核心将提供来自人类受试者的样本，并在PD的α-核蛋白小鼠原纤维模型中统一临床前研究的动物模型核心。阿拉巴马州乌德尔中心还具有与培训和外展有关的重要任务。我们试图培训下一代的科学家和医生，以加速前进的PD治疗和未来的治疗方法。我们将吸引与PD的人社区，他们是我们的合作伙伴。我们试图创建一个专注于识别对PD发病机理至关重要的先天和适应性免疫调查的团队和环境，并迅速提高创新，跨学科的，高度影响力的研究计划。