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：
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
项目类别：
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

项目摘要

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：总体正如报告中所述，制定帕金森病的神经保护策略是一项尚未得到满足的重要需求。 NINDS 理事会 (PD2014)，“专注于 PD 的研究人员群体现在致力于创造能够有意义地减缓或阻止导致帕金森病所有症状的疾病机制。” 该中心是对这些需求的回应，也是我们在 NINDS 探索性资助计划下工作的产物帕金森病研究 (P20NS092530)。人们早已认识到，在帕金森病死后的脑组织中，先天性神经元被激活。免疫系统，黑质中存在显着的小胶质细胞增生，同时产生增强的最近，人们已经清楚，适应性免疫也被激活。随着 T 细胞的浸润和神经周围区域免疫球蛋白的积累，我们设想更好的结果。了解帕金森病的免疫变化将确定具体的目标和治疗策略，以阻止神经变性。该计划项目将解决两个总体科学目标：1）确定早期人类 PD 中的免疫激活；2) 确定是否抑制 LRRK2 和 JAK/STAT 信号传导途径可以阻断与α-突触核蛋白相关的神经变性背后的免疫反应。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，在早期就被激活。疾病，并且阻断这些细胞中的 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、子集的详细研究免疫细胞和骨髓移植方法来检验这个假设。通过提供人类受试者样本的临床核心和提供人类受试者样本的动物模型核心协调 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还有与培训和外展相关的重要使命。下一代科学家和医生，以加速帕金森病治疗的进展我们将与帕金森病患者社区合作，他们是我们的合作伙伴。我们寻求创建一个专注于识别先天性和适应性免疫的团队努力和环境对 PD 发病机制至关重要的反应，并迅速推进创新、跨学科、高度影响力的研究研究计划。