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.

亚拉巴马尤德尔中心：总体 PD的神经保护策略的开发是一个重要的未满足的需求。正如提交给大会的报告所述， NINDS理事会（PD 2014），“专注于PD的研究者社区现在努力创造治疗方法， 有意义地减缓或停止PD所有症状的疾病机制。亚拉巴马尤德尔 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（P20 NS 092530）。 长期以来，人们已经认识到，在帕金森病的死后脑组织中， 免疫系统，黑质中有显著的小胶质细胞增生， 细胞因子和趋化因子。最近，已经清楚的是，也有适应性免疫的激活， 伴有T细胞浸润和免疫球蛋白在神经周围区域的积聚。我们设想一个更好的 了解PD的免疫变化将确定特定的靶点和治疗策略， 神经变性 该计划项目将解决两个总体科学目标：1）确定的程度和性质， 在早期人PD中的免疫激活;和2）确定抑制LRRK 2和JAK/STAT信号传导是否 通路可以阻断作为α-突触核蛋白相关神经变性基础的免疫应答。我们的中央 假设先天性和适应性免疫细胞，特别是单核细胞和T细胞，在免疫早期被激活， 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，亚群的详细研究， 免疫细胞和骨髓移植的方法来验证这一假设。每个项目都是锚定的 通过临床核心，将提供来自人类受试者的样本，和动物模型核心， 协调了PD的α-突触核蛋白小鼠原纤维模型中的临床前研究。 亚拉巴马尤德尔中心也有重要的任务有关的培训和推广。我们寻求训练 下一代科学家和医生，以加速PD治疗的进展 和未来的治疗方法。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，专注于识别先天性和适应性免疫 对PD发病机制至关重要的反应，并迅速推进一个创新的，跨学科的， 研究计划。