Discovering Small Molecule Activators of Stress-Responsive Signaling

项目总结 内质网(ER)应激与多种年龄相关疾病的发生和发病有关。 包括许多神经退行性疾病。在这些疾病中，内质网应激导致几乎所有 细胞生理学的各个方面。为了保护组织免受内质网压力，哺乳动物进化出了未折叠的蛋白质 反应(UPR)--由下游激活的三个信号臂组成的应激反应信号通路 ER膜胁迫敏感蛋白IRE1、ATF6和PERK。作为对内质网应激的反应，这些通路 被激活以促进多个生物通路的转录重塑，从而既减轻启动 ER侮辱和防止细胞生理上的病理性破坏。这种重塑主要是由 UPR相关转录因子XBP1s(激活的IRE1下游)和ATF6(裂解产物 全长ATF6)。这些转录因子调节与生物保护性有关的基因的表达。 途径包括那些影响细胞代谢、脂质调节、氧化还原和分泌蛋白平衡的途径。然而， 尽管UPR在保护细胞免受病理性内质网应激方面有效，但UPR信号转导的缺陷 由遗传、环境或衰老相关的侮辱引起的损害组织适应其生理的能力， 直接导致与许多不同类型的疾病有关的组织特异性病理。这表明 有选择地增强自适应、保护性的UPR信令代表着一个潜在的机会 内质网应激相关的病理与衰老和年龄相关疾病有关。与此一致的是，基因， 化学、生物学和体内证据表明，增强保护性IRE1/XBP1s或ATF6信号正确 许多不同的疾病都与特定的组织病理学有关。我们假设有选择性的， 药物激活保护性的IRE1/XBP1s或ATF6信号是一种很有前途的方法 治疗策略，以减轻衰老和许多与年龄相关的疾病的病理。超过了 在之前的资助期，我们利用基于细胞的表型高通量筛选(HTS)和全细胞 建立选择性激活适应性IRE1/XBP1s的一流化合物的转录图谱 或ATF6转录信号程序。这些化合物正被我们的实验室和全球30个实验室使用 定义药理IRE1/XBP1或ATF6的功能含义和治疗潜力的世界 年龄相关疾病的激活，包括蛋白质错误折叠障碍、缺血/再灌注损伤、眼睛 疾病、肥胖--糖尿病、癌症和神经退行性疾病，如阿尔茨海默病(AD)。这里, 我们扩展了这项研究，以建立下一代化合物，选择性地激活这些保护性UPR 通过明确的作用机制和改进的效力、疗效和药效学的途径 和药代动力学曲线，以增加它们在不同的实验和疾病模型中的应用。 此外，我们定义了这些化合物在衰老和AD小鼠模型中增强记忆的潜力， 揭示了通过药物激活UPR改善认知功能缺陷的新机会。

PROJECT SUMMARY Endoplasmic reticulum (ER) stress is implicated in the onset and pathogenesis of diverse age-related diseases, including many neurodegenerative disorders. In these diseases, ER stress leads to disruptions in nearly all aspects of cellular physiology. To protect tissues against ER stress, mammals evolved the unfolded protein response (UPR) – a stress-responsive signaling pathway comprising three signaling arms activated downstream of the ER membrane stress-sensing proteins IRE1, ATF6, and PERK. In response to ER stress, these pathways are activated to promote transcriptional remodeling of multiple biological pathways to both mitigate the initiating ER insult and prevent pathologic disruptions in cell physiology. This remodeling is primarily mediated by the UPR-associated transcription factors XBP1s (activated downstream of IRE1) and ATF6 (a cleaved product of full-length ATF6). These transcription factors regulate expression of genes involved in protective biological pathways including those effecting cell metabolism, lipid regulation, redox, and secretory proteostasis. However, despite the efficacy of the UPR in protecting cells against pathologic ER stress, deficiencies in UPR signaling induced by genetic, environmental, or aging-related insults impair the ability of tissues to adapt their physiology, directly contributing to tissue-specific pathologies implicated in many different types of disease. This suggests that selective enhancement of adaptive, protective UPR signaling represents a potential opportunity to mitigate ER stress-associated pathologies implicated in aging and age-related diseases. Consistent with this, genetic, chemical biologic, and in vivo evidence shows that enhancing protective IRE1/XBP1s or ATF6 signaling corrects tissue-specific pathologies implicated in many different maladies. We hypothesize that selective, pharmacological activation of protective IRE1/XBP1s or ATF6 signaling represents a promising therapeutic strategy to mitigate pathologies in aging and numerous age-related diseases. Over the previous funding period, we leveraged cell-based phenotypic high throughput screening (HTS) and whole cell transcriptional profiling to establish first-in-class compounds that selectively activate the adaptive IRE1/XBP1s or ATF6 transcriptional signaling programs. These compounds are being used by our lab and >30 labs around the world to define the functional implications and therapeutic potential of pharmacological IRE1/XBP1s or ATF6 activation in age-associated diseases including protein misfolding disorders, ischemia/reperfusion injury, eye diseases, obesity-diabetes, cancer, and neurodegenerative disorders such as Alzheimer’s disease (AD). Here, we expand this study to establish next generation compounds that selectively activate these protective UPR pathways, through defined mechanisms of action and with improved potency, efficacy, and pharmacodynamic and pharmacokinetic profiles, to increase their application across diverse experimental and disease models. Further, we define the potential for these compounds to enhance memory in mouse models of aging and AD, revealing new opportunities to ameliorate defects in cognitive function through pharmacologic UPR activation.