Androgen Modulation of Neurodegeneration in Dopamine Neurons

问题：帕金森病（PD）在男性人群中有较高的患病率。PD的特点是运动功能障碍、僵硬和运动迟缓。当前的研究表明性别扮演了一个角色在这种情况下,因为男性更有帕金森病的发病率。人们认为PD的潜在机制与氧化应激导致细胞凋亡有关。在许多外周细胞和一些神经细胞中，雄激素已被证明可增加细胞凋亡。目的：本研究的目的是通过体外和体内两种方法确定雄激素对氧化应激后多巴胺能细胞的影响。该提案的中心假设是雄激素增加了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：本提案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。第二个特定目的是评估雄激素对氧化应激后多巴胺能N27神经元中雌激素介导的神经保护的影响。这些目标将通过有或没有星形胶质细胞和雄激素受体拮抗剂羟氟他胺存在的体外分子研究来实现。最后，第三个特定目标将表征雄激素对暴露于6-OHDA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体内影响，6-OHDA诱导黑质和纹状体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，以及性腺切除的老年男性加替代雄激素（睾酮或双氢睾酮），在6-OHDA病变前进行慢性（3个月）或急性（1周）治疗。免疫细胞化学和行为技术将用于实现这一目标。结果：本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易感性的基本知识。最终，这些知识可以用来为理解神经退行性疾病中性别差异的机制提供基础。

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.