ESTROGEN AND PROGESTERONE SIGNALING PATHWAYS CONTROL INTRACELLULAR CALCIUM

最近的研究表明，类固醇激素雌激素和孕酮，它们的代谢产物，以及 化学衍生品起到保护细胞免受损伤和死亡的作用。在各种器官和细胞中 类型，这已被记录为急性侮辱和退化性疾病。在保护者中 由这些类固醇激素触发的机制是重新建立胞浆自由 钙离子动态平衡。这是细胞决定分化的重要把关人， 有丝分裂或凋亡严重依赖于细胞内钙通道(ICC)的活性，肌醇1，4， 5-三磷酸受体(IP3R)和兰尼定受体(RyR)。细胞内钙信号转导途径 这些通道可以通过急性和长期应用雌激素和/或黄体酮来特异性地改变。 目前的应用将检验类固醇激素调节细胞内钙信号的假设。 通过ICC，这对神经元功能和生存能力是重要的。尤其是雌激素的作用， 黄体酮和相关化合物将被评估它们诱导翻译后反应的能力。 修饰ICC，从而通过控制胞浆诱导神经保护相关的信号通路 游离钙离子动态平衡。这一点意义重大，因为它的非基因组效应 雌激素和孕激素，包括细胞内钙信号，有可能提供 设计与生理和临床相关的细胞保护策略所需的信息 影响神经系统的年龄相关疾病和包括阿尔茨海默氏症在内的神经退行性疾病 疾病(AD)。这项研究的总体目标是确定属于非基因组的新的信号通路 雌激素和孕激素在神经系统中的作用。这种新的治疗方法的鉴定 靶点将使我们能够在病理生理的细胞保护方面开发新的策略 衰老和阿尔茨海默病期间影响神经元的过程。 AD正在影响越来越多的人的健康和生活质量。此外，在 老龄化人口中的激素水平是阿尔茨海默病和其他年龄相关疾病的危险因素。这个 目前的提案解决了这些紧迫的健康问题，这些问题也是全机构NIH/NIA的重点 活动。拟议中的研究结果将使研究人员能够开发出更有效的治疗AD的药物 以及相关疾病和临床医生在激素替代治疗中使用更有效的治疗方法 治疗和与年龄有关的疾病，包括阿尔茨海默病。

Recent studies suggest that the steroid hormones estrogen and progesterone, their metabolic products, and chemical derivatives mediate protection against cellular damage and death. In a variety of organs and cell types, this has been documented for both acute insults and degenerative diseases. Among the protective mechanisms that are triggered by these steroid hormones is the re-establishment of the cytosolic free calcium ion homeostasis. This important gatekeeper of cellular decisions to progress towards differentiation, mitosis or apoptosis is critically dependent on the activity of intracellular calcium channels (ICC), inositol 1, 4, 5-trisphosphate receptor (IP3R) and ryanodine receptors (RyR). Intracellular calcium signaling mediated by these channels can be specifically altered by acute and chronic application of estrogen and/or progesterone. The present application will test the hypothesis that steroid hormones regulate intracellular calcium signaling through ICC that are important for neuronal function and viability. In particular, the effect of estrogen, progesterone, and related compounds, will be evaluated for their ability to induce posttranslational modifications of ICC and thereby elicit neuroprotection-related signaling pathways by controlling the cytosolic free calcium ion homeostasis. This is of high significance due to the fact that the non-genomic effects of estrogen and progesterone, which include intracellular calcium signaling, have the potential to provide the necessary information to design physiologically and clinically relevant cytoprotection strategies relevant for age-related disorders affecting the nervous systems and neurodegenerative diseases including Alzheimer's disease (AD). The overall goal of the study is to identify novel signaling pathways that are part of nongenomic actions of estrogen and progesterone in the nervous system. This identification of novel therapeutic targets will subsequently enable us to develop new strategies in cytoprotection for pathophysiological processes affecting neurons during aging and AD. AD is affecting the health and quality of life of an increasing number of individuals. In addition, changes in hormone levels in the aging population contribute as risk factors to AD and other age-related diseases. The present proposal addresses these pressing health issues that are also the focus of agency-wide NIH / NIA activities. Results from the proposed study will enable researchers to generate more effective drugs for AD and related diseases and clinicians to utilize more effective therapeutic approaches in hormone replacement therapy and in age related diseases including AD.