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（由申请人提供）：氧化应激和男性是导致帕金森病 (PD) 的两个常见风险因素。目前尚不清楚这些情况如何增加男性患帕金森病的风险。睾酮 (T) 参与调节这种性别差异，这一点值得关注，因为在过去十年中，老年男性的 T 疗法使用量增加了 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。 .在这个提案中，我们将研究 T 对黑质多巴胺神经元氧化应激产生的作用，这些神经元在 PD 进展过程中丢失，T 和氧化应激会共同促进 PD 进展，包括 NADPH。我们假设 T 和氧化应激之间的相互作用通过调节 PD 病理学这些方面的细胞信号通路增加 PD 发病机制。假设，我们提出了三个目标。在目标 1 中，我们将确定 G 蛋白偶联受体是否介导多巴胺能细胞系和早期 PD 动物模型中 T 诱导的氧化应激产生。在目标 2 中，我们将研究 T 是否增加。在多巴胺能细胞系和早期 PD 动物模型中，通过激活 NADPH 氧化酶（参与氧化应激产生的关键酶）来消除氧化应激。最后，在目标 3 中，我们将描述其特征。 T 对晚期 PD 动物模型中氧化应激产生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 PD 的多巴胺能神经功能的影响。 T 和氧化应激之间的相互作用以及它们如何促进男性 PD 进展此外，我们的研究将解决 NIH 医学研究所关于对老年男性进行更多 T 疗法研究的建议。