Exosomes and Neuroinflammation in Parkinsons Disease

外泌体和帕金森病的神经炎症

基本信息

批准号：
9207021
负责人：
ARTHI KANTHASAMY
金额：
$ 32.03万
依托单位：
IOWA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-02-01 至 2019-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9207021
关键词：
Address Affect Animal Disease Models Animal Model Animals Astrocytes Autopsy Biochemical Brain Brain Diseases Brain region Cell Culture Techniques Cells Chronic Data Development Disease model Dopamine Event Exposure to Functional disorder Goals Inflammasome Inflammatory Inflammatory Response Interleukin-1 beta Knockout Mice Maps Mediating Microglia Modeling Mole the mammal Molecular Mus Nerve Degeneration Neuroglia Neurons Outcome Outcome Study Parkinson Disease Partner in relationship Pathogenicity Pathologic Pathway interactions Phosphotransferases Play Process Production Protein Kinase Proteins Regulation Resistance Role Signal Transduction Site Small Interfering RNA Stress System Time Tissues Transgenic Mice Translating Up-Regulation Viral Wit alpha synuclein brain cell brain tissue chemokine cytokine effective therapy exosome genetic approach in vivo insight mRNA Expression man mutant neurochemistry neuroinflammation neuron loss neurotoxic nigrostriatal system novel novel therapeutics parkin gene/protein promoter protein aggregate protein aggregation public health relevance research study response transcription factor

项目摘要

DESCRIPTION (provided by applicant): Neuroinflammation has been implicated as a major pathophysiological process of Parkinson's disease (PD) in recent years. Among various neuroinflammatory triggers, protein aggregates have been shown to be a predominant pathological trigger for microglial activation and subsequent proinflammatory cytokine and chemokine production in the brain, which in turn con tributes to the accelerated progression of neurodegenerative processes. Also, emerging evidence indicates that aggregated pathogenic proteins, including α-synuclein (αSyn), are packaged into exosomes, which propagate protein aggregates from affected neurons to other brain cells, including microglial cells, through a non-cellular autonomous process, leading to a heightened neuroinflammatory response. Despite these advances, the cellular mechanisms underlying microglia-mediated neuroinflammatory events following stimulation with αSyn aggregates and αSyn-containing exosomes are yet to be defined. While studying kinase signaling in PD models, we unexpectedly discovered that the major non-receptor tyrosine kinase Fyn is rapidly activated in primary microglia within a few minutes of stimulation with the known inflammogen LPS. Interestingly, Fyn activation triggers proinflammatory responses, including cytokine/chemokine release from microglia. In addition, our preliminary findings revealed that aggregated αSyn also induced a rapid activation of Fyn kinase and the NLRP3 inflammasome. To further expand our novel preliminary results, we will systematically pursue the following specific aims: (i) to characterize the mechanism of Fyn kinase activation and its role in the regulation of NLRRP2/3 inflammasomes in microglia and astrocytes during inflammatory stress induced by αSyn aggregates and exosomes containing αSyn aggregates and to determine the proinflammatory role of Fyn in dopaminergic neuronal cell death, (ii) to define the molecular mechanisms underlying Fyn upregulation in microglia and astroglia during sustained inflammatory responses induced by αSyn aggregates and αSyn exosomes in animal models of PD, and (iii) to determine the role of Fyn in mediating the proinflammatory response in the nigrostriatal dopaminergic system during αSyn protein aggregation in animal models of PD as well as in postmortem PD brain tissues. Biochemical, cellular and neurochemical approaches will be used to achieve these specific aims. Taken together, delineating the role of Fyn kinase in αSyn protein aggregation-induced microglial activation will not only provide novel mechanistic insights into the progression of neurodegenerative processes in PD, but may also be useful for translating mechanistic outcomes into effective therapies for PD.

描述（由申请人提供）：近年来，神经炎症被认为是帕金森病（PD）的主要病理生理过程，在各种神经炎症触发因素中，蛋白质聚集体已被证明是小胶质细胞活化以及随后的促炎细胞因子和促炎性细胞因子的主要病理触发因素。此外，新出现的证据表明，包括 α-突触核蛋白在内的致病蛋白会聚集。 (αSyn)，被包装到外泌体中，通过非细胞自主过程将蛋白质聚集体从受影响的神经元传播到其他脑细胞，包括小胶质细胞，导致细菌神经炎症反应，尽管有这些进展，但小胶质细胞背后的细胞机制仍然存在。在研究 PD 模型中的激酶信号传导时，我们意外地发现了主要的非受体酪氨酸激酶 Fyn。在用已知的炎症原 LPS 刺激后几分钟内，Fyn 会在原代小胶质细胞中迅速激活，Fyn 激活会引发促炎症反应，包括小胶质细胞释放细胞因子/趋化因子。此外，我们的初步研究结果表明，聚集的 αSyn 还诱导了 Fyn 的快速激活。 Fyn 激酶和 NLRP3 炎症小体为了进一步扩展我们新的初步结果，我们将系统地追求以下具体目标：（i）表征 Fyn 激酶激活的机制及其在调节中的作用。 αSyn 聚集体和含有 αSyn 聚集体的外泌体诱导炎症应激期间小胶质细胞和星形胶质细胞中的 NLRRP2/3 炎性体，并确定 Fyn 在多巴胺能神经元细胞死亡中的促炎作用，(ii) 定义小胶质细胞和星形胶质细胞中 Fyn 上调的分子机制在 PD 动物模型中由 αSyn 聚集体和 αSyn 外泌体诱导的持续炎症反应，以及 (iii) 确定 Fyn 在在 PD 动物模型以及死后 PD 脑组织中，在 αSyn 蛋白聚集过程中介导黑质纹状体多巴胺能系统的促炎症反应，将用于实现这些特定目标，从而描述 Fyn 的作用。 αSyn 蛋白聚集诱导的小胶质细胞激活中的激酶不仅将为 PD 神经退行性过程的进展提供新的机制见解，而且还可能有助于翻译机制结果转化为有效的帕金森病治疗方法。