Intracellular calcium channels as targets of estrogen and progesterone

项目概要（见说明）：上一个供资期。项目3发现类固醇激素雌激素（E2）和孕酮（P4）在CNS神经元中引发保护机制，代表细胞溶质游离钙离子稳态重建的关键组成部分，导致深刻的神经保护。具体而言，E2和P4作为该机制的一部分能够通过诱导特异性翻译后修饰的不同激酶信号传导途径非基因组地改变细胞内钙通道的活性。然而，这些激素作为药物疗法的神经保护潜力的充分发展的关键障碍是其有限的治疗窗口和全身副作用。特别地，如许多开创性研究所示，使用类固醇激素来对抗在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个体绝经后的短时间段。此外，由于在男性和绝经后女性个体中的致癌和雌激素副作用，在整个生命周期中的有用性也非常有限。目前的竞争性更新重点关注这一机制，并且通过类固醇激素控制ICC的特定PTM状态来提高神经元活力。具体地，类固醇激素信号传导诱导这些修饰，并且与ICC功能相关的类固醇激素结合蛋白调节这种活性。特别是，将测量临床相关治疗窗口的神经保护性PTM的时程和可持续性;将确定替代治疗策略以诱导ICC的相同PTM，从而引起神经保护。这种策略可以绕过潜在的致癌和雌激素副作用。这是非常重要的，因为E2和P4对钙信号传导的影响，在以前的资助期间产生的数据，是影响神经系统和神经退行性疾病（包括AD）的年龄相关疾病的潜在临床相关细胞保护策略。当在临床相关的penods中独立产生时，即超出类固醇激素本身的治疗窗，这种作用代表了具有高度临床相关性的新治疗方法。本研究的总体目标是确定E2和P4在CNS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用性。这种创新策略具有显著的潜力，可以将类固醇介导的神经保护的狭窄治疗窗口扩展到临床相关的年龄范围，以实现针对CNS衰老和AD基础过程的神经保护。

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.