Prokineticin 2 and Neuroinflammatory Mechanisms

描述（由申请人提供）：神经炎症现在被认为是包括帕金森病（PD）在内的几种神经退行性疾病的关键退行性机制。神经炎性应激引起的神经元损伤的严重程度取决于脑内炎症和抗炎通路的失调程度。迄今为止，大多数研究都集中在确定在神经炎症损伤过程中激活的主要促炎通路。了解与大脑炎症的各个阶段相关的抗炎机制将为与神经退行性疾病相关的疾病过程提供新的见解。在这个建议中，我们的目标是描绘一个新的抗炎保护反应，在黑质纹状体多巴胺能神经元介导的最近发现的哺乳动物蛋白质同系物曼巴蛇毒液：原动力蛋白-2（PK 2）。出乎意料的是，我们观察到一个戏剧性的上调PK 2蛋白和它的释放从多巴胺能神经元细胞在炎症TNF损伤。进一步观察PD动物模型中黑质多巴胺能神经元以及死后PD患者黑质样本中PK 2表达增加，为我们的研究结果的临床意义提供了证据。有趣的是，重组PK 2显着保护神经元细胞凋亡和TH阳性多巴胺能神经元的损失引起的神经炎性损伤。令人惊讶的是，PK 2处理也促进星形胶质细胞和小胶质细胞的迁移。因此，在本提案中，我们打算扩大我们的初步意见，争取实现以下具体目标：（i）表征在原代细胞培养物和动物模型中，在炎性损伤后多巴胺能神经元中的PK 2诱导、释放和功能，（ii）确定在炎性刺激后PK 2诱导对星形胶质细胞和小胶质细胞迁移和功能的影响，（iii）研究神经细胞中PK 2上调的分子机制;（iv）在原代细胞培养和PD动物模型中证实PK 2的神经保护作用。细胞，分子和神经化学的方法将被用来描绘这些具体的目标。总之，了解炎症应激过程中多巴胺能神经元中PK 2上调和释放的作用不仅将提供有关黑质多巴胺能变性神经退行性机制的新见解，而且还可能产生治疗帕金森病的新治疗策略。

DESCRIPTION (provided by applicant): Neuroinflammation is now recognized as a key degenerative mechanism in several neurodegenerative diseases including Parkinson's disease (PD). The severity of neuronal damage caused by neuroinflammatory stress is dependent on the degree of dysregulation of inflammatory and anti-inflammatory pathways in brain. Most studies to date are focused on identifying major pro-inflammatory pathways that are activated during neuroinflammatory insult. Understanding the anti-inflammatory mechanisms associated with various stages of brain inflammation will provide new insights into disease processes associated with neurodegenerative diseases. In this proposal, we aim to delineate a novel anti-inflammatory protective response in the nigrostriatal dopaminergic neurons mediated by the recently discovered mammalian protein homolog of mamba snake venom: Prokineticin-2 (PK2). Unexpectedly, we observed a dramatic up-regulation of PK2 protein and its release from dopaminergic neuronal cells during inflammatory TNF¿ insult. Further observation of increased PK2 expression in nigral dopaminergic neurons in an animal model of PD as well as in the nigral samples from postmortem PD patients provides credence for the clinical significance of our findings. Interestingly, recombinant PK2 significantly protected against apoptotic neuronal cell death and TH positive dopaminergic neuronal loss induced by neuroinflammatory insults. Surprisingly, PK2 treatment also promoted migration of both astrocytes and microglial cells. Therefore, in this proposal, we intend to expand our preliminary observations by pursuing the following specific aims: (i) To characterize the PK2 induction, release and function in dopaminergic neurons following inflammatory insults in primary cell culture and animal models, (ii) To determine the effect of PK2 induction on astroglial and microglial migration and function following inflammatory stimuli, (iii) To investigate the molecular mechanisms of PK2 up-regulation in neuronal cells, and (iv) To demonstrate the neuroprotective effect of PK2 in primary cell culture and animal models of PD. Cellular, molecular and neurochemical approaches will be used to delineate these specific aims. Together, understanding the role of PK2 up-regulation and release during inflammatory stress in dopaminergic neurons will not only provide new insights about neurodegenerative mechanisms underlying nigral dopaminergic degeneration but may also yield novel therapeutic strategies for treatment of Parkinson's disease.