Intracellular calcium channels as targets of estrogen and progesterone

项目概述（见项目说明）：在上一个资助期内。项目3发现类固醇激素雌激素（E2）和孕酮（P4）在中枢神经系统神经元中引发一种保护机制，这是重建胞质游离钙离子稳态的关键组成部分，从而产生深远的神经保护作用。具体来说，E2和P4作为这一机制的一部分，能够通过不同的激酶信号通路，诱导特定的翻译后修饰，非基因组地改变细胞内钙通道的活性。然而，充分发挥这些激素作为药物治疗的神经保护潜力的一个关键障碍是它们有限的治疗窗口和全身副作用。特别是，一些开创性的研究表明，使用类固醇激素来对抗衰老和阿尔茨海默病（AD）期间影响神经元的疾病过程仅限于女性绝经后的短时间内。此外，由于男性和绝经后女性个体的致癌和雌激素副作用，其有效性在整个生命周期中也极为有限。目前的竞争性更新集中在这一机制上，并且通过类固醇激素控制ICCs特定PTMs的状态来提高神经元活力。具体来说，类固醇激素信号传导诱导这些修饰，类固醇激素结合蛋白与icc功能相关，调节这种活性。特别是，神经保护性PTMs的时间过程和可持续性将被测量为临床相关的治疗窗口；将确定替代治疗策略，以诱导ICC相同的PTMs，从而引起神经保护。这种策略可以避免潜在的致癌和雌激素副作用。这是非常重要的，因为E2和P4对钙信号的影响，在之前的资助期产生的数据，是潜在的临床相关的细胞保护策略，用于影响神经系统的年龄相关疾病和包括AD在内的神经退行性疾病。当在临床相关的阴茎中独立产生时，即超出类固醇激素本身的治疗窗口，这种效应代表了具有高度临床相关性的新型治疗方法。该研究的总体目标是确定E2和P4在中枢神经系统中的非基因组作用以及类固醇激素控制的钙信号蛋白的可药物性。这一创新策略具有巨大的潜力，将类固醇介导的神经保护的狭窄治疗窗口扩大到临床相关的年龄范围，以实现对中枢神经系统老化和AD潜在过程的神经保护。

PROJECT SUMMARY (See instructions): In the previous funding period. Project 3 discovered that the steroid hormones estrogen (E2) and progesterone (P4) elicit a protective mechanism in CNS neurons representing a critical component of the reestablishment of the cytosolic free calcium ion homeostasis resulting in profound neuroprotection. Specifically, E2 and P4 as part of this mechanism are capable of changing the activity of intracellular calcium channels non-genomically through distinct kinase signaling pathways that induce specific post-translational modifications. However, a critical impediment to the full development of the neuroprotective potential of these hormones as pharmacotherapies is their limited therapeutic window and systemic side-effects. In particular, the use of steroid hormones to combat disease processes affecting neurons during aging and Alzheimer's disease (AD) is limited to a short time period after menopause in female individuals as shown by a number of seminal studies. In addition, usefulness is also extremely limited throughout the lifespan due to carcinogenic and estrogenic side-effects in male and postmenopausal female individuals. The present competitive renewal focuses on this mechanism and that improved neuronal viability is generated by steroid hormones controlling the state of specific PTMs of ICCs. Specifically, steroid hormone signaling induces these modifications and steroid hormone binding proteins functionally associated with ICCs modulate this activity. In particular, the time course and sustainability of neuroprotective PTMs will be measured for clinically relevant therapeutic windows; alternative therapeutic strategies will be determined to induce the same PTMs of ICC and thereby elicit neuroprotection. This strategy can bypass potential carcinogenic and estrogenic side-effects. This is of high significance because such effects of E2 and P4 on calcium signaling, data generated in the previous funding period, are potential clinically relevant cytoprotection strategies for age-related disorders affecting the nervous systems and neurodegenerative diseases including AD. When generated independently in clinically relevant penods, i.e. beyond the therapeutic window of steroid hormones themselves, such effects represent novel therapeutic approaches with high clinical relevance. The overall goal of the study is to identify the druggability of non-genomic actions of E2 and P4 in the CNS and of steroid hormone controlled calcium signaling proteins. This innovative strategy has a significant potential to expand the narrow therapeutic window for steroid mediated neuroprotection into an age range that is clinically relevant to achieve neuroprotection against processes underlying CNS aging and AD.