Androgen Modulation of Neurodegeneration in Dopamine Neurons

描述(申请人提供)：问题：帕金森氏病(PD)在人类男性人群中有较高的患病率。帕金森病的特征是运动功能障碍、僵硬和运动迟缓。目前的研究表明，性别在这种情况下起到了一定的作用，因为男性患帕金森病的几率更高。人们认为帕金森病的潜在机制涉及氧化应激导致细胞凋亡。在许多外周细胞和一些神经细胞中，雄激素已经被证明增加了细胞的凋亡。目的：通过体外和体内两种方法研究雄激素对氧化应激后多巴胺能细胞的影响。这一建议的中心假设是雄激素增加了细胞对氧化应激诱导的多巴胺能神经元神经毒性的易感性。研究问题：这项建议的第一个具体目标是确定氧化应激(过氧化氢)后雄激素激活的多巴胺能n27细胞中的凋亡信号通路。第二个具体目的是评估雄激素对氧化应激后多巴胺能n27神经元雌激素介导的神经保护的影响。这些目标将通过在有或没有星形胶质细胞和雄激素受体拮抗剂羟基氟他胺存在的情况下进行体外分子研究来实现。最后，第三个具体目标将表征体内雄激素对6-OHDA暴露的老年雄性大鼠酪氨酸羟化酶表达、神经元死亡和运动行为的影响，6-OHDA可诱导黑质和纹状体的氧化应激和细胞凋亡。体内激素治疗组将包括性腺切除的老年男性，性腺完好的老年男性，以及性腺切除的老年男性加上替代雄激素(睾酮或双氢睾酮)，在6-OHDA损伤之前进行慢性(3个月)或急性(1周)治疗。将使用免疫细胞化学和行为技术来实现这一目标。结果：这项研究将提供有关雄激素如何调节多巴胺能细胞对氧化应激的脆弱性的基本知识。最终，这些知识可以用来为理解神经退行性疾病中潜在的性别差异机制提供基础。

DESCRIPTION (provided by applicant): PROBLEM: Parkinson's disease (PD) has a higher prevalence in the human male population. PD is characterized by motor dysfunction, rigidity, and bradykinesia. Current research suggests that gender plays a role in this condition, since males have a greater incidence of PD. It is believed that the underlying mechanism of PD involves oxidative stress leading to cellular apoptosis. In many peripheral cells and some neuronal cells, androgens have been shown to increase apoptosis. PURPOSE: The goal of these studies is to determine androgen's effects on dopaminergic cells following oxidative stress by using both in vitro and in vivo methods. The central hypothesis of this proposal is that androgens increase cellular vulnerability to oxidative stress-induced neurotoxicity in dopaminergic neurons. RESEARCH QUESTIONS: The first specific aim of this proposal is to determine the apoptotic signaling pathways activated by androgens in dopaminergic N27 cells following oxidative stress (hydrogen peroxide). The second specific aim is designed to evaluate the effects of androgens on estrogen-mediated neuroprotection in dopaminergic N27 neurons following oxidative stress. These aims will be accomplished through in vitro molecular studies with and without the presence of astroglia cells and the androgen receptor antagonist, hydroxyflutamide. Lastly, the third specific aim will characterize the in vivo effects of androgens on tyrosine hydroxylase expression, neuronal death, and motor behavior in aged male rats exposed to 6-OHDA, which induces oxidative stress and apoptosis in the substantia nigra and striatum. In vivo hormone treatment groups will consist of gonadectomized aged males, gonadally intact aged males, and gonadectomized aged males plus replacement androgen (testosterone or dihydrotestosterone) for either a chronic (3 months) or acute (1 week) treatment time length prior to 6-OHDA lesion. Immunocytochemical and behavioral techniques will be used to accomplish this aim. OUTCOMES: This study will provide basic knowledge on how androgens modulate dopaminergic cellular vulnerability to oxidative stress. Ultimately, this knowledge can be used to provide a foundation to understanding the mechanisms underlying sex differences in neurodegenerative disorders.