Exosomes and Neuroinflammation in Parkinsons Disease

外泌体和帕金森病的神经炎症

• 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
• 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

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(申请人提供)：近年来，神经炎症被认为是帕金森病(PD)的一个主要病理生理过程。在各种神经炎性诱因中，蛋白质聚集体被证明是脑内小胶质细胞激活和随后的促炎性细胞因子和趋化因子产生的主要病理诱因，这反过来又导致神经退变过程的加速进展。此外，新的证据表明，聚集的致病蛋白，包括α-突触核蛋白(αSyn)被包装到外体中，外体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包括小胶质细胞在内的其他脑细胞，导致神经炎症反应增强。尽管取得了这些进展，但小胶质细胞在αSyn聚合体和包含αSyn的外切体刺激下介导的神经炎性事件的细胞机制尚未确定。在研究帕金森病模型中的激酶信号时，我们出人意料地发现，主要的非受体酪氨酸激酶Fyn在已知的致炎原内毒素刺激后的几分钟内在初级小胶质细胞中迅速激活。有趣的是，Fyn的激活触发了促炎反应，包括从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显示，聚集型αSyn还可诱导Fyn激酶和NLRP3炎性小体的快速激活。为了进一步扩大我们的新的初步结果，我们将系统地追求以下具体目标：(I)在αSyn聚集体和含有αSyn聚集体的外切体诱导的炎症应激过程中，表征Fyn激酶激活的机制及其在小胶质细胞和星形胶质细胞中调控NLRRP2/3炎症小体的作用，并确定Fyn在多巴胺能神经元死亡中的促炎作用；(Ii)确定在αSyn聚集体和αSyn外切体诱导PD动物模型持续炎症反应中小胶质和星形胶质细胞Fyn上调的分子机制。以及(Iii)在帕金森病动物模型和死后帕金森病脑组织中，确定Fyn在αSyn蛋白聚集过程中在黑质纹状体多巴胺能系统中的促炎反应中的作用。将使用生化、细胞和神经化学方法来实现这些具体目标。综上所述，阐明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将为帕金森病神经退变过程的进展提供新的机制见解，而且可能有助于将机制结果转化为有效的帕金森病治疗方法。