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

项目摘要/摘要：项目2 神经炎症是帕金森病(PD)的主要致病因素。先天免疫和获得性免疫 包括小胶质细胞、巨噬细胞和CD4+T细胞在内的细胞参与了帕金森病。JAK/STAT路径是 细胞因子使用的主要信号通路，对免疫反应的调节至关重要。我们的结果 证明JAK/STAT通路的过度激活导致先天和适应性的失调 免疫反应，导致AAV2-α-突触核蛋白(SYN)的神经炎症和神经变性 模特。重要的是，JAK1/2抑制剂(Jakinib)AZD1480的治疗可以预防 神经炎性和神经退行性反应。此外，我们有初步数据表明 帕金森病患者单核细胞、CD4+T细胞和CD8+T细胞JAK/STAT信号通路的异常 与对照组相比，观察到性别差异。我们假设在帕金森氏病中，α-SYN的异常形式 引起JAK/STAT通路的激活改变，导致致病性先天免疫和获得性免疫 回应。这些事件会促进神经炎症和神经变性，并表明 对JAK/STAT通路的治疗干预将改变人类帕金森病的进展。 阿拉巴马州Udall中心的项目2将研究JAK/STAT途径的异常如何在 一种新的临床前帕金森病模型(目标1)和帕金森病患者(目标2)促进两者先天调节失调 和适应性免疫细胞，以及这对神经炎性反应和神经变性的影响。 我们已经证明，使用对JAK1/2具有特异性的Jakinib(AZD1480)对AAV2-α具有保护作用。 SYN PD模型。目标1将评估在新的α-SYN中靶向JAK/STAT通路的效果 纤毛(SPFF)模型，与人类帕金森病密切相关。我们将测试两个新的Jakinibs，它们都是专门针对 JAK1，一个是脑穿透性的，另一个不是。这些新的试剂将使我们能够确定 JAK1、JAK2或两者共同参与帕金森病的发病机制，并检测外周抑制信号是否 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 人PD中的Jak/STAT通路在髓系细胞、CD4+T细胞和CD8+T细胞中的检测 来自未经治疗的新生帕金森病患者的细胞。这些研究将使我们能够评估JAK/STAT通路 功能障碍发生在帕金森病的早期阶段，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，建议的研究将针对 帕金森病患者尚未回答的问题：外周和/或脑中JAK/STAT通路的激活 神经炎症和神经退行性变的重要因素？

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?