Developmental Factors for Reducing Dopamine Loss in Primate Models of PD & Aging

减少灵长类 PD 模型中多巴胺损失的发育因素

• 批准号: 9027986
• 负责人: JOHN D ELSWORTH
• 金额: $ 47.32万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9027986
• 关键词: Adenosine Monophosphate; Adolescent; Adult; Aging; Agonist; Animal Model; Antioxidants; Biochemical; Biochemical Pathway; Biomedical Research; Brain; Brain Diseases; Cercopithecus tantalus; Characteristics; Cognitive; Corpus striatum structure; Cyclic AMP; Data; Development; Disease; Dopamine; Dose; Drug usage; Elderly; Employee Strikes; Environment; Enzymes; Female; Foundations; Goals; Human; Impaired cognition; Incidence; Infant; Injection of therapeutic agent; Knowledge; Lead; Life; Ligands; Link; Mental disorders; Methamphetamine; Midbrain structure; Mission; Mitochondria; Modeling; Monkeys; Motor; National Institute of Child Health and Human Development; Oxidative Stress; PPAR gamma; Paraoxonase-2; Parkinson Disease; Parkinsonian Disorders; Pathway interactions; Pharmaceutical Preparations; Play; Population; Predisposition; Primates; Property; Prosencephalon; Protein Kinase; Publishing; Quercetin; Reactive Oxygen Species; Regulation; Research; Research Personnel; Resistance; Resources; Rodent; Role; Signal Transduction; Staging; Symptoms; Testing; Time; Toxic effect; UCP2 protein; Universities; Up-Regulation; Work; age related; base; clinically relevant; cognitive function; dopamine system; dopaminergic neuron; experience; falls; in vivo; male; medical schools; nanoparticle; nerve supply; nervous system disorder; neuron development; neuroprotection; nigrostriatal system; nonhuman primate; normal aging; novel; novel strategies; oxidative damage; prevent; public health relevance; resilience; response; species difference; stressor; therapy development; treatment strategy

 DESCRIPTION (provided by applicant): In normal human brain the population of midbrain dopaminergic neurons falls by about 3-5% every decade, while in Parkinson's disease (PD) this decline is much greater. This inexorable loss of dopamine (DA) innervation to forebrain regions has been firmly linked with declines in both motor and cognitive functions. Despite knowing that oxidative stress is a key conspirator in the loss of DA neuron function in PD and aging, there are no treatments to halt the attrition of DA neurons. Part of this problem is due to the inadequacy of animal models. Adult DA neurons are very susceptible to the parkinsonian-like oxidative stress exerted by either MPTP or methamphetamine (METH), but our group has demonstrated that for a restricted period early in life, the primate brain is remarkably resistant to such damage. This provides a new neuroprotection model for DA neurons, possessing "built-in" resilience to oxidative damage. The existence of this window of protection against MPTP or METH cannot be explained by altered drug levels, or by immaturity of key transporters or enzymes necessary for the toxic effect of the drugs. The goal of this project is to understand the factors and mechanisms shielding young primate DA neurons from oxidative stress and use this knowledge to provide protection to DA neurons at the later vulnerable stages of life. This approach promises to be successful as it relies on reinstating extant anti-oxidant mechanisms, rather than attempting to protect DA neurons using drugs that may manipulate biochemical signaling non-physiologically. We have identified 2 potential "juvenile protection factors" that are preferentialy expressed in the young primate brain and have strong anti-oxidant properties; uncoupling protein-2 (UCP2) and paraoxonase-2 (PON2). One aim tests the hypothesis that UCP2 plays a major role in mitigating the level of mitochondrial reactive oxygen species and subsequent damage to young DA neurons, and that 5' adenosine monophosphate-activated protein kinase (AMPK) activity regulates UCP2. Another aim examines the protection against induced oxidative stress in adult DA neurons that is achieved by using novel agents to activate UCP2 expression in vivo. Less is known about PON2 than UCP2, and the final aim will test hypotheses about its regulation and its role in protecting young primate DA neurons against oxidative stress damage, and will also examine to what extent up-regulation of PON2 expression in the adult affords protection against in vivo oxidative stress in DA neurons. In addition, we will pursue our data on male-female differences in expression of these juvenile protection factors in primate brain, as this may relate to the lower incidence of PD in female subjects and also provide new ways to induce protection in DA neurons. This proposal will pursue these novel directions using biochemical, histochemical, and pharmacological studies in vervet monkeys. The timing of critical milestones in developing DA neurons display important species differences, so these primate studies have particular translational relevance. This research is expected to stimulate new approaches to prevent the occurrence or progression of DA-dependent age-related disorders.

 描述（由申请人提供）：在正常人脑中，中脑多巴胺能神经元的数量每十年下降约 3-5%，而在帕金森病 (PD) 中，这种下降幅度要大得多。前脑区域多巴胺（DA）神经支配的不可避免的丧失与运动和认知功能的下降密切相关。尽管我们知道氧化应激是帕金森病和衰老过程中 DA 神经元功能丧失的关键因素，但目前还没有治疗方法可以阻止 DA 神经元的损耗。这个问题的部分原因是由于 动物模型。成年 DA 神经元非常容易受到 MPTP 或甲基苯丙胺 (METH) 产生的帕金森样氧化应激的影响，但我们的研究小组已经证明，在生命早期的一段有限时间内，灵长类动物的大脑对这种损伤具有显着的抵抗力。这为 DA 神经元提供了一种新的神经保护模型，具有“内置”的氧化损伤恢复能力。这种针对 MPTP 或 METH 的保护窗口的存在不能用药物水平的改变或药物毒性作用所需的关键转运蛋白或酶的不成熟来解释。该项目的目标是了解保护年轻灵长类 DA 神经元免受氧化应激的因素和机制，并利用这些知识为生命后期脆弱阶段的 DA 神经元提供保护。这种方法有望取得成功，因为它依赖于恢复现有的抗氧化机制，而不是试图使用可能以非生理方式操纵生化信号传导的药物来保护 DA 神经元。我们发现了2种潜在的“幼年保护因子”，它们优先在幼年灵长类动物大脑中表达，并具有很强的抗氧化特性；解偶联蛋白 2 (UCP2) 和对氧磷酶 2 (PON2)。一个目标测试了以下假设：UCP2 在减轻线粒体活性氧水平和随后对年轻 DA 神经元的损伤方面发挥着重要作用，并且 5' 腺苷单磷酸激活蛋白激酶 (AMPK) 活性调节 UCP2。另一个目标是检查对成人 DA 神经元诱导氧化应激的保护作用，这是通过使用新型药物激活体内 UCP2 表达来实现的。与 UCP2 相比，人们对 PON2 的了解较少，最终目标将测试有关其调节及其在保护年轻灵长类动物 DA 神经元免受氧化应激损伤中的作用的假设，并将检查成年 PON2 表达的上调在多大程度上提供了 DA 神经元体内氧化应激的保护。此外，我们将追踪灵长类大脑中这些幼年保护因子表达的男女差异数据，因为这可能与雌性受试者中 PD 发生率较低有关，并提供诱导 DA 神经元保护的新方法。该提案将利用黑长尾猴的生化、组织化学和药理学研究来探索这些新方向。发育 DA 神经元的关键里程碑的时间显示出重要的物种差异，因此这些灵长类动物研究具有特殊的转化相关性。这项研究有望激发新的方法来预防 DA 依赖性年龄相关疾病的发生或进展。