Prokineticin 2 and Neuroinflammatory Mechanisms

Prokineticin 2 和神经炎症机制

基本信息

批准号：
8658161
负责人：
ARTHI KANTHASAMY
金额：
$ 31.53万
依托单位：
IOWA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-15 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8658161
关键词：
1-Methyl-4-phenylpyridinium Address Animal Model Anti-Inflammatory Agents Anti-inflammatory Apoptotic Astrocytes Autopsy Biological Assay Brain Brain region Cell Culture Techniques Cells Coculture Techniques DNA Fragmentation Data Dendroaspis Disease Encephalitis Gene Expression Goals Homologous Protein Inflammatory Measures Mediating Microglia Midbrain structure Migration Assay Modeling Molecular Molecular Profiling Mus Nerve Degeneration Neurodegenerative Disorders Neuroglia Neurons Parkinson Disease Pathway interactions Patients Pattern Physiological Primary Cell Cultures Process Proteins Recombinants Reporter Research Role Sampling Severities Signal Transduction Signaling Molecule Small Interfering RNA Snake Venoms Staging Stimulus Stress System TNF gene Tissues Transduction Gene Transgenic Mice Up-Regulation Viral Wound Healing caspase-3 chemokine clinically relevant clinically significant cytokine dopaminergic neuron in vivo insight knockout animal migration neurochemistry neuroinflammation neuron loss neurotoxic novel novel therapeutic intervention novel therapeutics overexpression promoter receptor release factor response treatment strategy

项目摘要

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.

描述（由适用提供）：神经炎症现在被认为是包括帕金森氏病（PD）在内的几种神经退行性疾病中的关键退化机制。神经炎性应激引起的神经元损伤的严重程度取决于大脑炎症和抗炎途径的失调程度。迄今为止，大多数研究都集中在确定与脑感染各个阶段相关的神经炎症机制中被激活的主要促炎途径，这将为与神经退行性疾病相关的疾病过程提供新的见解。在该提案中，我们旨在描绘由近来发现的乳蛇毒毒素的哺乳动物蛋白质同源物介导的黑质多巴胺能神经元中的新型抗炎保护反应：Prokineticin-2（PK2）。出乎意料的是，我们观察到PK2蛋白的急剧上调及其在炎症性TNF期间从多巴胺能神经元细胞中释放出来。进一步观察到PD动物模型以及验尸后PD患者的nigral样品中PK2表达增加的增加，为我们发现的临床意义提供了证书。有趣的是，重组PK2受到神经炎症性损伤诱导的凋亡神经元细胞死亡和阳性多巴胺能神经元丧失。令人惊讶的是，PK2处理还促进了星形胶质细胞和小胶质细胞的迁移。因此，在这项建议中，我们打算通过追求以下具体目的来扩展我们的初步观察：（i）在原发性细胞培养和动物模型中炎症性损伤损伤后，在多巴胺能神经元中表征PK2诱导，释放和功能，（ii）对PK2诱导对摩尔型和微胶质迁移的影响（II），以确定炎症和微胶质迁移的影响（神经元细胞中PK2上调的机制，以及（iv）证明PK2在原代细胞培养和PD动物模型中的神经保护作用。细胞，分子和神经化学方法将用于描述这些特定目的。总之，了解多巴胺能神经元中PK2上调和释放在炎症性压力中的作用不仅会提供有关ni虫多巴胺能变性的神经退行性机制的新见解，而且还可能产生新的治疗策略来治疗帕金森氏病的治疗。