Estrogens, Ovarian Aging and Calcium Channel Modulation

雌激素、卵巢衰老和钙通道调节

• 批准号: 8828054
• 负责人: WILLIAM H GRIFFITH
• 金额: $ 27.82万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-15 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8828054
• 关键词: Adult; Age-associated memory impairment; Aging; Behavioral; Biological; Calcium Channel; Cognitive; Controlled Environment; Dementia; Estrogen Therapy; Estrogens; Female; Future; G-Protein-Coupled Receptors; Genomics; Goals; Health Care Costs; Image; Impaired cognition; Inbred F344 Rats; Incidence; Individual; Instruction; Menopause; MicroRNAs; Modeling; Molecular; Neurons; Operative Surgical Procedures; Ovarian; Pharmacotherapy; Phosphoric Monoester Hydrolases; Phosphotransferases; Physiology; Play; Postmenopause; Rattus; Risk; Role; Running; Signal Transduction; Site; Stroke; Testing; Water; Western Blotting; Woman; basal forebrain cholinergic neurons; cognitive function; neuronal excitability; non-genomic; postsynaptic; presynaptic; research study; restoration; senescence; synaptic function

Estrogen plays a fundamental role in neuronal physiology during aging, and declining estrogens at menopause increase the incidence of stroke, cognitive impairment and inflamhiation. While estrogen therapy (ET) is beneficial in young females or following surgical menopause, ET is detrimental in older, postmenopausal females. We believe that aging and the associated dysregulation of the horriional environment controls this dichotomy by alteration of pre-and postsynaptic s exerts its biological actions through both genomic and hoh-genorriicrriechanisms. the genomid actions of estrogens have been studied for decades, but rapid, non-genomic actions only recently haye been shown to control neuronal excitability, intracellular Ca2+ signaling, and kinase/phosphatase activity through G-protein coupled receptors. The goal: of the present proposal is to use. a rat model of ovarian aging and menopause to test the non-genomic estrogenic mechanisms that control Ga2+ and synaptic function against a background of ET with individual cognitive assessrnent:Vye hypothesize that, during ovarian aging, non-genomic (membranedelimited) estrogen signaling declines at pre- and postsynaptic sites in basal forebrain (BF) cholinergic neurons and that this deficit is inequitably rescued at pre- and postsynaptic sites by ET in reproductively senescent subjects. Unequal restoration of pre- and postsynaptic rapid estrogen signaling could contribute to cognitive dysfunction. We will use functibhal (jaatch clamp recording, fluorescent imaging), behavioral (water maze), and molecular approaches (Western blotting, Rt-PCR, microRNA analyses) to test this hypothesis in female F344 rats: mature multigravid adults (MA, 5-6 mo) and reproductively senescent (RS, 14-17 mo) subjects. MA and RS will be subdivided into^ovanectomized control:(dVX) and OVX +estrogen (OVX+E) groups. BF cholinergic neurons will be targeted because they; are responsive to ET and are important in age-related cognitive decline. Our experiments will define the non-genomic actions of estrogens and how these actions are modulated by ovarian aging and ET, Identification of aberrant estrogen signaling will provide an important first step in ideritifying potential targets for future drug therapies..

雌激素在衰老过程中在神经生理学中起着重要作用， 更年期增加中风、认知障碍和炎症的发病率。虽然雌激素治疗 (ET)在年轻女性或手术绝经后是有益的，ET在老年人中是有害的， 绝经后女性我们相信衰老和相关的激素调节失调 环境通过改变突触前和突触后S发挥其 通过基因组和高分子机制的生物学作用。雌激素的基因组作用 已经研究了几十年，但快速的，非基因组的行动，直到最近才被证明可以控制 神经元兴奋性、细胞内Ca 2+信号传导和激酶/磷酸酶活性通过G蛋白偶联 受体。本提案的目标是使用。一个卵巢老化和绝经的大鼠模型来测试 在ET背景下控制Ga 2+和突触功能的非基因组雌激素机制 与个体认知评估：Vye假设，在卵巢老化过程中，非基因组（膜限制） 雌激素信号在基底前脑（BF）胆碱能神经元突触前和突触后部位下降， 神经元，这种赤字是不公平的救援，在前和突触后网站的ET在生殖 衰老的实验对象突触前和突触后快速雌激素信号的不平等恢复可能有助于 认知功能障碍我们将使用functibhal（jaatch钳记录，荧光成像），行为（水 迷宫）和分子方法（Western印迹，RT-PCR，microRNA分析）来测试这一假设， 雌性F344大鼠：成熟的多次妊娠成年大鼠（MA，5-6个月）和生殖衰老大鼠（RS，14-17个月） 科目MA和RS将被细分为去卵巢对照：（dVX）和OVX +雌激素（OVX+E） 组BF胆碱能神经元将被靶向，因为它们对ET有反应，并且在 与年龄相关的认知能力下降我们的实验将确定雌激素的非基因组作用以及如何 这些作用受到卵巢衰老和ET的调节，对异常雌激素信号传导的鉴定将 为确定未来药物治疗的潜在靶点迈出了重要的第一步。