Androgen Modulation of Neurodegeneration in Dopamine Neurons

描述（由申请人提供）：问题：帕金森病（PD）在男性人群中的患病率较高。PD的特征在于运动功能障碍、僵硬和运动迟缓。目前的研究表明，性别在这种情况下发挥作用，因为男性有更大的PD发病率。据信，PD的潜在机制涉及导致细胞凋亡的氧化应激。在许多外周细胞和一些神经细胞中，雄激素已被证明可以增加细胞凋亡。目得：这些研究的目的是通过使用体外和体内方法来确定雄激素对氧化应激后多巴胺能细胞的影响。该建议的中心假设是，雄激素增加多巴胺能神经元对氧化应激诱导的神经毒性的细胞脆弱性。研究问题：该建议的第一个具体目的是确定氧化应激（过氧化氢）后多巴胺能N27细胞中雄激素激活的凋亡信号通路。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作用的影响。这些目标将通过体外分子研究来实现，有和没有星形胶质细胞和雄激素受体拮抗剂，羟基氟替卡松的存在。最后，第三个具体目标将表征雄激素对暴露于6-OHDA的老年雄性大鼠的酪氨酸羟化酶表达、神经元死亡和运动行为的体内影响，6-OHDA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、性腺完整的老年男性和性腺切除的老年男性加6-OHDA损伤前长期（3个月）或急性（1周）治疗时间长度的替代雄激素（睾酮或双氢睾酮）。免疫细胞化学和行为学技术将用于实现这一目标。结果：这项研究将提供关于雄激素如何调节多巴胺能细胞对氧化应激的脆弱性的基础知识。最终，这些知识可以用来提供一个基础，了解神经退行性疾病的性别差异的机制。

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.