Project 2: Validating the JAK/STAT Pathway as a Novel Therapeutic Strategy in PD

项目 2：验证 JAK/STAT 通路作为 PD 的新型治疗策略

基本信息

批准号：
10469388
负责人：
Etty N Benveniste
金额：
$ 37.99万
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/10469388
关键词：
Adaptive Immune System Address Age Alabama Basic Science Blood Brain Brain imaging CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cells Clinical Clinical Research Cognition Cohort Analysis Collaborations Complement Data Disease model Evaluation Event Flow Cytometry Functional disorder Generations Genes Genetic Transcription Human Immune Immune response Incidence Infiltration Inflammation Inflammatory Injections Interferon Type II Interleukin-6 Interruption JAK1 gene JAK2 gene Microglia Modeling Myeloid Cells Natural Immunity Nerve Degeneration Neurobehavioral Manifestations Outcome Parkinson Disease Pathogenesis Pathogenicity Pathology Pathway interactions Patients Peripheral Phenotype Population Pre-Clinical Model Production Rattus Reagent Regulation Research Project Grants Resolution Sex Differences Signal Pathway Signal Transduction Specificity Symptoms System T cell differentiation Testing Therapeutic Therapeutic Intervention Treatment Efficacy Virulence Factors Woman adaptive immune response adaptive immunity alpha synuclein brain cell cellular imaging cohort cytokine design dopaminergic neuron efficacy evaluation efficacy validation human model immune function immunoregulation in vivo inhibitor longitudinal analysis macrophage men monocyte neuroinflammation new therapeutic target novel novel therapeutic intervention pre-clinical prevent protective effect recruit response sex single-cell RNA sequencing targeted treatment transcriptome sequencing

项目摘要

PROJECT SUMMARY/ABSTRACT: PROJECT 2 Neuroinflammation is a major pathogenic factor in Parkinson Disease (PD). Both innate and adaptive immune cells, including microglia, macrophages and CD4+ T-cells, are involved in PD. The JAK/STAT pathway is the major signaling pathway used by cytokines, and is critical for regulation of immune responses. Our results demonstrate that hyperactivation of the JAK/STAT pathway causes dysregulation of innate and adaptive immune responses, leading to neuroinflammation and neurodegeneration in the AAV2-α-synuclein (syn) model. Importantly, therapeutic treatment with a JAK1/2 inhibitor (Jakinib), AZD1480, prevented neuroinflammatory and neurodegenerative responses. Furthermore, we have preliminary data demonstrating dysregulation of the JAK/STAT pathway in monocytes, CD4+ T-cells and CD8+ T-cells from patients with PD compared to controls, with observed sex differences. We hypothesize that in PD, abnormal forms of α-syn cause altered activation of the JAK/STAT pathway, leading to pathogenic innate and adaptive immune responses. These events promote neuroinflammation and neurodegeneration, and suggest that therapeutic intervention in the JAK/STAT pathway will alter the progression of human PD. Project 2 of the Alabama Udall Center will examine how abnormalities in the JAK/STAT pathway in the context of a new pre-clinical PD model (Aim 1) and in patients with PD (Aim 2) promote dysregulation of both innate and adaptive immune cells, and how that impacts on the neuroinflammatory response and neurodegeneration. We have demonstrated that use of a Jakinib with specificity for JAK1/2 (AZD1480) is protective in the AAV2-α- syn PD model. Aim 1 will be the evaluation of targeting the JAK/STAT pathway in the new α-syn preformed fibril (sPFF) model, that closely models human PD. We will test two novel Jakinibs which are both specific for JAK1, with one being brain penetrant and the other not. These novel reagents will allow us to determine the involvement of JAK1, JAK2 or both in PD pathogenesis, and test whether inhibiting signaling in the periphery is sufficient for protective effects. In Aim 2, we will directly test our hypothesis that there is dysregulation of the JAK/STAT pathway in human PD by examination of this pathway in myeloid cells, CD4+ T-cells and CD8+ T- cells from untreated, de novo PD patients. These studies will allow us to assess whether JAK/STAT pathway dysfunction occurs at the earliest stages of PD, and if this predicts more rapid progression of clinical symptoms, with a focus on cognitive symptoms. Collectively, the proposed studies will address an unanswered question in PD: is activation of the JAK/STAT pathway in the periphery and/or brain an important contributor to neuroinflammation and neurodegeneration?

项目摘要/摘要：项目2 神经炎症是帕金森氏病（PD）的主要致病因素。先天和适应性免疫包括小胶质细胞，巨噬细胞和CD4+ T细胞在内的细胞参与PD。 jak/stat途径是细胞因子使用的主要信号通路，对于调节免疫反应至关重要。我们的结果证明JAK/STAT途径的过度激活会导致先天和适应性的失调免疫反应，导致AAV2-α-核蛋白（SYN）的神经炎症和神经变性模型。重要的是，用JAK1/2抑制剂（Jakinib）AZD1480治疗治疗神经炎症和神经退行性反应。此外，我们有初步数据证明 PD患者的单核细胞，CD4+ T细胞和CD8+ T细胞中JAK/STAT途径的失调与对照组相比，观察到的性别差异。我们假设在PD中，α-Syn的异常形式导致JAK/STAT途径的激活改变，导致致病性和适应性免疫回答。这些事件促进了神经炎症和神经变性，并建议在JAK/STAT途径中的治疗干预将改变人类PD的进展。阿拉巴马州乌德尔中心的项目2将检查jak/stat途径中的异常情况新的临床前PD模型（AIM 1）和PD患者（AIM 2）促进了两者先天的失调和自适应免疫电池，以及这如何影响神经炎症反应和神经变性。我们已经证明，在AAV2-α-中保护具有特异性的Jakinib（AZD1480）受到保护。 SYN PD模型。 AIM 1将评估针对新α-Syn中的JAK/STAT途径原纤维（SPFF）模型，密切建模人类PD。我们将测试两个新颖的jakinibs JAK1，一个是脑渗透物，另一个是脑渗透物。这些新颖的试剂将使我们能够确定 JAK1，JAK2或两者都参与PD发病机理，并测试抑制周围信号是否为足以受到保护的影响。在AIM 2中，我们将直接检验我们的假设，即存在失调通过检查髓样细胞，CD4+ T细胞和CD8+ T-的该途径的JAK/STAT途径来自未治疗的从头PD患者的细胞。这些研究将使我们能够评估JAK/STAT途径是否功能障碍发生在PD的最早阶段，如果这种预测的临床进展更快症状，重点是认知症状。拟议的研究集体将解决 PD中的未解决问题：在周围和/或大脑中激活JAK/STAT途径神经炎症和神经变性的重要贡献者？