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（由适用提供）：近年来，神经炎症已作为帕金森氏病（PD）的主要病理生理过程实施。在各种神经炎性触发器中，蛋白质聚集体已被证明是小胶质细胞激活以及随后的促炎细胞因子和大脑中趋化因子产生的主要病理触发因素，这反过来又致力于神经变性过程的加速进展。同样，新兴的证据表明，包括α-突触核蛋白（αSyn）在内的聚集的致病蛋白被包装到外泌体中，这些蛋白质通过非脑细胞自治过程传播从受影响的神经元到其他脑细胞的蛋白质聚集体，从而通过非细胞自主性过程，导致神经神经炎的高度响应。尽管有这些进展，但在用αSyn聚集体刺激和含αSyn的外泌体刺激后，小胶质细胞介导的神经炎症事件的细胞机制尚未定义。在研究PD模型中的激酶信号传导的同时，我们出乎意料地发现，在已知的炎症LPS刺激的几分钟内，在原代小胶质细胞中迅速激活了主要的非受体酪氨酸激酶FYN。有趣的是，FYN激活会触发促炎反应，包括从小胶质细胞中的细胞因子/趋化因子释放。此外，我们的初步发现表明，聚集的αSyn还诱导了FYN激酶和NLRP3炎性体的快速激活。 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多巴胺能神经元细胞死亡，（ii）定义在小胶质细胞和星形胶质细胞中Fyn上调的分子机制，这是在αsyn骨料和αSyn骨料诱导的持续炎症反应中，以及Pd动物模型中的αsyn骨料中的αSyn骨架，以及（III）的作用（III），以确定fymAINTIAR的作用。在PD动物模型以及验尸PD脑组织中的αSyn蛋白聚集期间。生化，细胞和神经化学方法将用于实现这些特定目标。综上所述，描述FYN激酶在αSyn蛋白聚集诱导的小胶质细胞激活中的作用不仅会为PD中神经退行性过程的进展提供新颖的机械见解，而且还可用于将机械脱落转化为PD的有效疗法。