Interactions between testosterone and oxidative stress in dopamine neurons

 描述（由申请人提供）：帕金森病（PD）发展的两个常见风险因素是氧化应激和男性。目前尚不清楚这些情况如何增加男性PD的风险。我们的数据表明，主要的男性性激素，睾酮（T），参与介导这种性别差异。这是令人担忧的，因为在过去的十年中，T疗法的使用在老年男性中增加了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。在这个提议中，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。假设T和氧化应激协同增加PD进展。T和氧化应激都影响PD病理学的关键特征，包括NADPH氧化酶和α-突触核蛋白积累。我们假设T和氧化应激之间的相互作用通过调节PD病理这些方面的细胞信号传导途径增加PD发病机制。为了研究这些假设，我们提出了三个目标。在目的1中，我们将确定G蛋白偶联受体是否介导T诱导的多巴胺能细胞系和早期PD动物模型中的氧化应激产生。在目标2中，我们将研究T是否通过激活NADPH氧化酶（参与氧化应激产生的关键酶）在多巴胺能细胞系和早期PD动物模型中增加氧化应激。最后，在目标3中，我们将描述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和氧化应激对多巴胺能神经元功能的影响，从早期到晚期PD。我们研究的完成将从机制上定义T和氧化应激之间的相互作用，以及它们如何促进男性PD进展。此外，我们的研究将解决美国国立卫生研究院医学研究所的建议，更多的研究T治疗老年男性。

 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.