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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：
10469383
负责人：
DAVID G. STANDAERT
金额：
$ 187.3万
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 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10469383
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 Hyperactivity 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 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 outcome measures clinical predictors cohort cytokine genetic approach genome analysis human subject imaging study immune activation immune function inhibitor 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.

帕金森病（PD）的神经保护策略的发展是一个重要的未满足的需求。正如提交给NINDS理事会的报告（PD 2014）中所述，“专注于PD的研究者群体目前正在努力创造有意义地减缓或停止PD所有症状背后的疾病机制的疗法”。亚拉巴马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（P20 NS 092530）下工作的产物。长期以来，人们已经认识到，在PD的死后脑组织中，存在先天免疫系统的激活，黑质中具有显著的小胶质细胞增生，以及细胞因子和趋化因子的产生增强。最近，已经清楚的是，也存在适应性免疫的激活，伴随着T细胞的浸润和免疫球蛋白在神经周围区域的积累。我们设想，更好地了解PD中的免疫变化将确定阻断神经变性的特定靶点和治疗策略。该中心将致力于两个总体科学目标：1）确定早期人类PD中免疫激活的程度和性质; 2）确定抑制LRRK 2和JAK/STAT信号通路是否可以阻断作为α-突触核蛋白相关神经变性基础的免疫反应。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LRRK 2或JAK/STAT信号传导将防止神经变性。我们将利用先进的小分子配体和抑制剂，遗传学方法，免疫细胞亚群的详细研究和骨髓移植方法来验证这一假设。每个项目都通过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临床前研究的动物模型核心进行锚定。亚拉巴马尤德尔中心也有重要的任务有关的培训和推广。我们致力于培养下一代科学家和医生，以加速PD治疗和未来治愈的进展。我们将与PD社区的人谁是我们的合作伙伴在这些努力。我们寻求创建一个团队和环境，专注于识别对PD发病机制至关重要的先天和适应性免疫反应，并迅速推进创新，跨学科，高度影响力的研究计划。