Androgen Modulation of Neurodegeneration in Dopamine Neurons

雄激素对多巴胺神经元神经变性的调节

• 批准号: 7558485
• 负责人: REBECCA L CUNNINGHAM
• 金额: $ 2.1万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7558485
• 关键词: Acute; Androgen Receptor; Androgens; Apoptosis; Apoptotic; Astrocytes; Behavior; Behavioral; Bradykinesia; Cells; Cessation of life; Chronic; Corpus striatum structure; Dopaminergic Cell; Estrogens; Foundations; Functional disorder; Gender; Goals; High Prevalence; Hormones; Hydrogen Peroxide; In Vitro; Incidence; Knowledge; Length; Lesion; Mediating; Methods; Molecular; Motor; Muscle Rigidity; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Oxidative Stress; Oxidopamine; Parkinson Disease; Peripheral; Play; Population; Rattus; Research; Role; Sex Characteristics; Signal Pathway; Stanolone; Substantia nigra structure; Techniques; Testosterone; Time; Tyrosine 3-Monooxygenase; aged; design; dopaminergic neuron; human male; hydroxyflutamide; in vivo; male; neuroprotection; neurotoxicity

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.

描述（由申请人提供）： 问题：帕金森病 (PD) 在男性人群中患病率较高。 PD 的特征是运动功能障碍、强直和运动迟缓。目前的研究表明，性别在这种情况下发挥着重要作用，因为男性患帕金森病的发病率更高。据信PD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元细胞中，雄激素已被证明可以增加细胞凋亡。目的：这些研究的目的是通过体外和体内方法确定氧化应激后雄激素对多巴胺能细胞的影响。该提议的中心假设是，雄激素增加了多巴胺能神经元中细胞对氧化应激诱导的神经毒性的脆弱性。研究问题：本提案的第一个具体目标是确定氧化应激（过氧化氢）后多巴胺能 N27 细胞中雄激素激活的细胞凋亡信号通路。第二个具体目标是评估氧化应激后雄激素对雌激素介导的多巴胺能 N27 神经元神经保护的影响。这些目标将通过体外分子研究来实现，无论是否存在星形胶质细胞和雄激素受体拮抗剂羟基氟他胺。最后，第三个具体目标将描述雄激素对暴露于 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 会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以及性腺切除的老年男性加替代雄激素（睾酮或二氢睾酮），治疗时间长度为6-6之前的慢性（3个月）或急性（1周）。 OHDA 病变。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础知识。最终，这些知识可以为理解神经退行性疾病性别差异的机制奠定基础。