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

项目总结/摘要：项目2 神经炎症是帕金森病（PD）的主要致病因素。先天性和适应性免疫 细胞，包括小胶质细胞、巨噬细胞和CD 4 + T细胞参与PD。JAK/STAT通路是 细胞因子使用的主要信号传导途径，并且对于调节免疫应答至关重要。我们的结果 证明JAK/STAT途径的过度激活会导致先天性和适应性调节失调 免疫应答，导致AAV 2-α-突触核蛋白（syn）中的神经炎症和神经变性 模型重要的是，使用JAK 1/2抑制剂（Jakinib）AZD 1480进行治疗， 神经炎症和神经变性反应。此外，我们有初步数据表明， PD患者单核细胞、CD 4 + T细胞和CD 8 + T细胞中JAK/STAT通路的失调 与对照组相比，观察到性别差异。我们假设在帕金森病中，异常形式的α-syn 引起JAK/STAT通路的激活改变，导致致病性先天性和适应性免疫 应答这些事件促进神经炎症和神经变性，并表明， JAK/STAT途径的治疗性干预将改变人PD的进展。 亚拉巴马尤德尔中心的项目2将研究JAK/STAT通路的异常如何在 新的临床前PD模型（目的1）和PD患者（目的2）促进两种先天性 和适应性免疫细胞，以及它们如何影响神经炎症反应和神经变性。 我们已经证明，使用对JAK 1/2具有特异性的Jakinib（AZD 1480）在AAV 2-α- syn PD模型。目的1将是评价在新的α-syn中靶向JAK/STAT通路 原纤维（sPFF）模型，其紧密地模拟人类PD。我们将测试两个新的Jakinibs，这两个都是特定的， JAK 1，其中一个是大脑渗透剂，另一个不是。这些新的试剂将使我们能够确定 JAK 1、JAK 2或两者参与PD发病机制，并测试抑制外周信号传导是否是 足以起到保护作用。在目标2中，我们将直接测试我们的假设，即存在着对神经元的调节障碍。 通过在骨髓细胞、CD 4 + T细胞和CD 8 + T细胞中检查JAK/STAT通路， 来自未经治疗的原发性PD患者的细胞。这些研究将使我们能够评估JAK/STAT通路是否 功能障碍发生在PD的最早阶段，如果这预示着临床进展更快， 症状，重点是认知症状。总的来说，拟议的研究将解决一个 PD中未回答的问题：外周和/或大脑中JAK/STAT通路的激活是否 神经炎症和神经变性的重要贡献者？

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?