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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：
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.

阿拉巴马尤德尔中心：总体而言