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：
10119067
负责人：
DAVID G. STANDAERT
金额：
$ 37.13万
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/10119067
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.

正如向 NINDS 理事会提交的报告 (PD2014) 中所述，开发帕金森病 (PD) 的神经保护策略是一项重要的未满足需求，“专注于帕金森病的研究人员现在正在努力开发能够有效减缓或阻止该疾病的疗法。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下工作的产物。 (P20NS092530)。人们早就认识到，在PD死后脑组织中存在先天免疫系统的激活，黑质中存在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。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 PD 的免疫变化将识别出特定的免疫变化。该中心将解决两个总体科学目标：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断我们的中心假设是，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，并阻断 LRRK2 或 JAK/STAT 信号传导。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该假设，每个项目都以提供样本的临床核心为基础。来自人类受试者的动物模型核心协调了 PD α-突触核蛋白小鼠原纤维模型的临床前研究，阿拉巴马州尤德尔中心也有与培训和推广相关的重要任务。一代科学家和医生，以加速未来帕金森症治疗和治愈的进展，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，我们寻求创建一个专注于识别先天和帕金森病的团队和环境。适应性免疫反应对 PD 发病机制至关重要，并迅速推进创新、跨学科、有影响力的研究计划。