Neuroinflammation and microglial Kv1.3 in Parkinsons disease

帕金森病中的神经炎症和小胶质细胞 Kv1.3

• 批准号: 10528896
• 负责人: Anumantha Gounder Kanthasamy
• 金额: $ 37.35万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10528896
• 关键词: Neuroinflammation; microglial; Kv1.3; Parkinsons; disease

A sustained neuroinflammatory insult characterized by massive microglia activation has been well recognized as a major pathophysiological contributor to the progression of neurodegenerative processes in Parkinson’s disease (PD). Interestingly, microglia constitute a particularly attractive therapeutic target for PD because elevated microglia activation is evident during the early stages of PD pathogenesis preceding dopaminergic degeneration. Recent studies pertaining to neuroinflammation in PD have generated tremendous enthusiasm because α-synuclein (αSn) aggregates can serve as an endogenous antigen triggering neurotoxicity by provoking a potent microglia-mediated proinflammatory response. Also, accumulating evidence reveals that misfolded αSyn spreads through a cell-to-cell transmission mechanism, contributing to the propagation of α yn pathology to neighboring neuronal and glial cells, possibly augmenting the progression of PD. Despite these advances, the fundamental neurobiological mechanisms regulating sustained microglia activation and neuroinflammatory cascades during pathogenic αSyn aggregate stimulation remain to be established. Thus, identification of key targets contributing to sustained microglia activation could provide potential targets to slow the progression of the disease. We recently obtained exciting new data showing that the voltage-gated potassium channel Kv1.3 is highly upregulated in aggregated αSyn-stimulated primary microglia and animal models of PD, as well as in human PD postmortem samples. Importantly, patch-clamp electrophysiological studies confirmed that the observed Kv1.3 upregulation translates to increased Kv1.3 channel activity. Additional preliminary results suggest that a proinflammatory kinase PKCδ plays a role in αSyn aggregate-induced Kv1.3 upregulation. To further expand our novel preliminary results, we will systematically pursue the following specific aims: (i) characterize Kv1.3 upregulation and activation of pro-inflammatory microglia in animal models of αSyn aggregate-induced neurotoxicity, and define the role of Kv1.3 in microglia-mediated neuroinflammation and augmentation of the neurodegenerative process in nigrostriatal dopaminergic neurons in PD, (ii) unravel the molecular underpinning of Kv1.3 channel upregulation in microglia during an αSyn aggregate-induced neuroinflammatory insult, and (iii) establish the role of Kv1.3 in mediating the proinflammatory response in the nigrostriatal dopaminergic system during αSyn protein aggregation in animal models of PD. We will use multiple model systems and state-of-the-art biochemical, cellular, neurophysiological, histological and neurochemical approaches to achieve these specific aims. Overall, we anticipate that our proposed studies will provide novel mechanistic insights into sustained microglia activation and its role in neuroinflammatory processes in PD disease progression and will offer novel therapeutic targets to curtail neuroinflammatory responses in PD and other related neurodegenerative disorders.

以大量小胶质细胞激活为特征的持续的神经炎症损伤已被公认为是 帕金森氏病（PD）中神经退行性过程进展的主要病理生理学贡献。有趣的是，小胶质细胞构成了PD的特别有吸引力的治疗靶点，因为在多巴胺能变性之前的PD发病机理的早期，小胶质细胞激活升高。与PD中神经炎症有关的最新研究引起了极大的热情，因为α-突触核蛋白（αSN）聚集体可以通过引起潜在的微胶质细胞介导的促症促症反应来充当触发神经毒性的内源性抗原。此外，积累的证据表明，αSyn散布错误 通过细胞到细胞的传播机制，导致αYN病理传播到相邻神经元和神经胶质细胞，可能会增强PD的进展。尽管有这些进展，但在致病性αSyn骨料刺激期间，基本的神经生物学机制调节了持续的小胶质细胞激活和神经炎症级联反应。这是鉴定导致持续小胶质细胞激活的主要靶标可以提供潜在的靶标，以减缓疾病的发展。最近，我们获得了令人兴奋的新数据，表明电压门控钾通道KV1.3在聚集的αSyn刺激的原代小胶质细胞和PD的动物模型以及人类PD验尸中高度更新 样品。重要的是，斑块钳电生理研究证实，观察到的KV1.3上调转化为KV1.3通道活性的增加。其他初步结果表明，促炎激酶PKCδ在αSyn骨料诱导的KV1.3上调中起作用。为了进一步扩大我们新的初步结果，我们将系统地追求以下具体目的：（i）特征KV1.3在αSyn聚集的动物模型中，KV1.3促炎性小胶质细胞的上调和激活在αSyn聚集的神经毒性中，并定义了KV1.3在微胶质介导的神经介导的神经化和增生剂中的作用PD中的多巴胺能神经元，（ii）在αSyn骨料诱导的神经炎性感染过程中阐明KV1.3小胶质细胞中KV1.3通道上调的分子基础，（iii）在介导非染色体膜中的动物膜脉络性反应中的作用中，在介导非杂质的促进性反应中的作用。 PD。我们将使用多种模型系统以及最先进的生化，细胞，神经生理学，组织学和神经化学方法来实现这些特定目标。总体而言，我们预计我们的拟议研究将为持续的小胶质细胞激活及其在其中的作用提供新的机械见解 PD疾病进展中的神经炎症过程，将为PD和其他相关神经退行性疾病的神经炎症反应提供新的治疗靶点。