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Interactions between testosterone and oxidative stress in dopamine neurons

睾酮与多巴胺神经元氧化应激之间的相互作用

基本信息

批准号：
9277584
负责人：
REBECCA L CUNNINGHAM
金额：
$ 31.94万
依托单位：
UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9277584
关键词：
Address Affect Aging Androgen Antagonists Androgen Receptor Androgens Animal Disease Models Animal Model Apoptosis Apoptotic Autopsy Brain Calcium Cell Line Cell membrane Cells Chronic Comorbidity Coupled Data Development Disease Disease Progression Disease model Dopamine Dopaminergic Cell Drug Targeting Elderly Environment Enzymes Estrogen Antagonists Functional disorder Future G-Protein-Coupled Receptors GTP-Binding Protein alpha Subunits, Gs Gender Generations Goals Gonadal Steroid Hormones Hypoxia Individual Institute of Medicine (U.S.)Knowledge Lead Mediating Membrane Metabolism Mission Modeling Motor NADPH Oxidase Nerve Degeneration Neurodegenerative Disorders Neurons Neurotoxins Oxidases Oxidation-Reduction Oxidative Stress Paraquat Parkinson Disease Pathogenesis Pathology Patients Protein Isoforms Public Health Publishing Rattus Recommendation Research Risk Risk Factors Role Signal Pathway Signal Transduction Sleep Apnea Syndromes Substantia nigra structure System Testosterone Therapeutic Toxic effect United States National Institutes of Health Woman Work age related alpha synuclein brain tissue cell type clinical risk clinically relevant disorder risk dopaminergic neuron gender difference high risk male men neurotoxic novel public health relevance receptor response therapeutic development

项目摘要

DESCRIPTION (provided by applicant): Two common risk factors for the development of Parkinson's disease (PD) are oxidative stress and male gender. It is unclear how these conditions increase the risk for PD in men. Our data suggests that the major male sex hormone, testosterone (T), is involved in mediating this gender difference. This is of concern as T therapy use has increased 3-fold in aging men just this past decade, yet we know little about how T impacts brain vulnerability to age-related disorders. In this proposal, we will investigate the rol of T on oxidative stress generation in substantia nigral dopamine neurons, which are lost during PD progression. T and oxidative stress are hypothesized to cooperatively increase PD progression. Both T and oxidative stress affect key features of PD pathology, including NADPH oxidases and α-synuclein accumulation. We postulate that an interaction between T and oxidative stress increases PD pathogenesis through cell signaling pathways that regulate these aspects of PD pathology. To investigate these hypotheses, we propose three aims. In Aim 1, we will determine whether a G-protein coupled receptor mediates T induced oxidative stress generation in a dopaminergic cell line and an early stage PD animal model. In Aim 2, we will investigate if T increases oxidative stress by activating NADPH oxidases, key enzymes involved in oxidative stress generation, in a dopaminergic cell line and early stage PD animal model. Finally, in Aim 3 we will characterize the effects of T on oxidative stress generation in an advanced stage PD animal model. These three aims will allow us to examine the effects of T and oxidative stress on dopaminergic neuronal function from early stage to advanced stage PD. Completion of our studies will mechanistically define interactions between T and oxidative stress and how they promote PD progression in men. Further, our studies will address the NIH Institute of Medicine's recommendation for more research on T therapy in aging men.

描述(申请人提供)：帕金森氏病(PD)发展的两个常见风险因素是氧化应激和男性性别。目前尚不清楚这些情况如何增加男性患帕金森病的风险。我们的数据表明，主要的男性荷尔蒙--睾酮(T)参与了这种性别差异的调节。这一点令人担忧，因为在过去的十年里，T疗法在老年男性中的使用量增加了3倍，但我们对T如何影响大脑对年龄相关疾病的脆弱性知之甚少。在这个方案中，我们将研究T在黑质多巴胺神经元氧化应激产生中的作用，这些神经元在帕金森病进展过程中丢失。T和氧化应激被认为协同增加帕金森病进展。T和氧化应激都影响帕金森病的关键病理特征，包括NADPH氧化酶和α-突触核蛋白积聚。我们推测，T和氧化应激之间的相互作用通过调节PD病理的这些方面的细胞信号通路增加了PD的发病。为了研究这些假设，我们提出了三个目标。在目标1中，我们将确定G蛋白偶联受体是否在多巴胺能细胞系和早期帕金森病动物模型中介导T诱导的氧化应激产生。在目标2中，我们将在多巴胺能细胞系和早期帕金森病动物模型中，研究T是否通过激活NADPH氧化酶来增加氧化应激，NADPH氧化酶是参与氧化应激产生的关键酶。最后，在目标3中，我们将在晚期帕金森病动物模型中表征T对氧化应激生成的影响。这三个目标将使我们能够检查T和氧化应激对从早期到晚期帕金森病的多巴胺能神经元功能的影响。我们研究的完成将从机械上定义T和氧化应激之间的相互作用，以及它们如何促进男性帕金森病的进展。此外，我们的研究将满足NIH医学研究所的建议，即对老年男性的T疗法进行更多研究。