Compensatory Mitochondrial Protective Mechanisms Against Oxidative Stress in PD

PD 中氧化应激的补偿性线粒体保护机制

基本信息

批准号：
10453241
负责人：
ARTHI KANTHASAMY
金额：
$ 43.6万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-15 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10453241
关键词：
Address Affect American Animal Model Biogenesis Biological Models Brain-Derived Neurotrophic Factor CREB1 gene Cell Culture Techniques Cell Nucleus Cell Survival Cell model Cells Chemicals Cognitive deficits Complex Disease Disease Progression Disease model Exhibits Genetic Transcription Goals Histologic Histone Deacetylase Human Inflammatory Response Mediating Mitochondria Modeling Molecular Mus Nature Nerve Degeneration Neurodegenerative Disorders Neurons Neurotoxins Nuclear Nuclear Accidents Nuclear Protein Nuclear Translocation Outcomes Research Oxidative Stress Parkinson Disease Pathologic Pathway interactions Peptides Phosphotransferases Predisposition Process Protein Kinase Protein translocation Protein-Serine-Threonine Kinases Quality Control Reporting Research Role Signal Pathway Signal Transduction Stress System Testing Time Transcriptional Regulation Up-Regulation conditional knockout dopaminergic neuron effective therapy factor A improved innovation mitochondrial dysfunction mitopark mouse motor deficit mouse model mtTF1 transcription factor neurochemistry neuroinflammation neuronal survival nigrostriatal system novel oxidative damage preclinical efficacy prevent programs protein activation relating to nervous system response stem therapeutic target transcription factor translational approach translational potential treatment strategy

项目摘要

Abstract The complex and prolonged disease course exhibited by Parkinson’s disease (PD) first starts with non-motor disturbances and then slowly progresses to mild-to-moderate motor deficits, ultimately inflicting severe motor and cognitive deficits. Although pathophysiological mechanisms underlying various stages of the disease have yet to be characterized, both mitochondrial dysfunction (MD) and neural oxidative stress (OS) have been identified as key pathological correlates in the progressive neurodegenerative process in PD. While studying key oxidative signaling mechanisms that regulate susceptibility of the nigrostriatal dopamin(DA)ergic system to MD and oxidative damage, we unexpectedly discovered that protein kinase D1 (PKD1) is highly expressed in nigral DAergic neurons and that the kinase is rapidly activated during the early stages of oxidative insult to protect DAergic neurons against oxidative damage. Our mechanistic studies revealed that activated PKD1 rapidly translocates to both mitochondria and the nucleus of DAergic neurons. Our preliminary studies show that activated PKD1 likely enhances the transcription of key neuro-adaptive oxidative mechanisms involving enhanced PGC1-α, TFAM and BDNF signaling pathways. Thus, the goal of this study is to elucidate mitochondrial/nuclear events governing the PKD1-mediated compensatory protective response using cell and animal models of PD. The overarching hypothesis of our proposal is that the pro-survival kinase PKD1 is rapidly activated in nigral DAergic neurons during the initial stage of an oxidative insult and quickly translocates to mitochondria and nuclei to initiate cell survival signaling pathways. Its nuclear translocation initiates key pro- survival transcriptional machinery responsible for PGC1-α, TFAM and BDNF upregulation, leading to enhanced mitochondrial biogenesis and neurotrophic support in DAergic neurons. Mitochondrial translocation of PKD1 improves mitochondrial function by regulating mitochondrial quality control (MQC). Thus, PKD1 serves as a key ‘compensatory adaptive switch’ in nigral DAergic neurons. To test this, we will systematically pursue the following specific aims: (i) characterize PKD1 activation and nuclear/mitochondrial translocation and its functional relevance in cell culture and animal models of PD; (ii) characterize the downstream pro-survival signaling pathways activated by PKD1 mitochondrial/nuclear translocation in DAergic neurons; and (iii) validate PKD1 as a therapeutic target of PD and examine the translational potential of a novel PKD1 activator. We will use multiple model systems and state-of-the-art cellular, histological and neurochemical approaches to achieve these specific aims. Our multifaceted approach to harness the PKD1 adaptive signaling mechanisms that promote DAergic neuronal survival will enable us to devise a novel translational strategy capable of intervening early in the course of disease progression in PD.

抽象的帕金森氏病（PD）暴露的复杂且长期的疾病病程首先从非运动开始干扰，然后慢慢发展为轻度到中度电动机定义，最终造成严重电机和认知缺陷。尽管疾病各个阶段的病理生理机制尚待表征，线粒体功能障碍（MD）和神经氧化应激（O）均已在PD的进行性神经退行性过程中被确定为关键病理相关性。在研究钥匙的同时氧化信号传导机制，这些机制调节骨纹状体多巴胺（DA）ERGIC系统对MD的敏感性和氧化损伤，我们意外地发现蛋白激酶D1（PKD1）在nigral中高度表达 Daergic神经元，并在氧化损伤的早期阶段迅速激活激酶以保护抗氧化损伤的daergic神经元。我们的机械研究表明，激活的PKD1迅速易位到线粒体和脂类神经元的核。我们的初步研究表明活化的PKD1可能会增强关键神经自适应氧化机制的转录增强的PGC1-α，TFAM和BDNF信号通路。这是这项研究的目的是阐明使用细胞和 PD的动物模型。我们提案的总体假设是亲苏生激酶PKD1迅速在氧化物侮辱的初始阶段，在ni核硫酸神经元中激活，并迅速易位线粒体和核启动细胞存活信号通路。它的核易位启动了关键的亲负责PGC1-α，TFAM和BDNF上调的生存转录机械，导致增强 Daergic神经元中的线粒体生物发生和神经营养支持。 PKD1的线粒体易位通过调节线粒体质量控制（MQC）来改善线粒体功能。那，PKD1充当钥匙 nigral daergic神经元中的“补偿性自适应开关”。为了测试这一点，我们将系统地追求以下具体目的：（i）表征PKD1激活和核/线粒体易位及其功能与PD的细胞培养和动物模型相关；（ii）表征下游促生物信号传导 Daergic神经元中的PKD1线粒体/核易位激活的途径；（iii）验证PKD1为 PD的治疗靶标，并检查新型PKD1激活剂的翻译潜力。我们将使用多个模型系统以及最先进的细胞，组织学和神经化学方法，以实现这些特定目标。我们利用PKD1自适应信号传导机制来促进DAERGIC的多方面方法神经元的生存将使我们能够制定一种能够在课程初期进行干预的新型翻译策略 PD疾病进展。