Discovering Small Molecule Activators of Stress-Responsive Signaling

项目摘要 内质网（ER）应激与多种年龄相关疾病的发病和发病机制有关， 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应激，哺乳动物进化了未折叠蛋白质 应激反应（UPR）-一种应激反应信号通路，包括下游激活的三个信号臂 ER膜应激敏感蛋白IRE 1、ATF 6和PERK。为了应对内质网应激，这些通路 被激活以促进多种生物学途径的转录重塑， ER损伤并防止细胞生理学中的病理性破坏。这种重塑主要是由 UPR相关的转录因子XBP 1（在IRE 1下游激活）和ATF 6（UPR的裂解产物） 全长ATF 6）。这些转录因子调节参与保护性生物学作用的基因的表达。 这些途径包括影响细胞代谢、脂质调节、氧化还原和分泌性蛋白质稳态的途径。然而，在这方面， 尽管UPR在保护细胞免受病理性ER应激方面具有功效，但UPR信号传导的缺陷 由遗传、环境或衰老相关的损伤诱导的损伤损害了组织适应其生理学的能力， 直接导致与许多不同类型疾病有关的组织特异性病理。这表明 选择性增强自适应、保护性UPR信号传递是缓解 ER应激相关病理与衰老和年龄相关疾病有关。与此相一致的是，基因， 化学生物学和体内证据表明，增强保护性IRE 1/XBP 1或ATF 6信号传导可以纠正 与许多不同疾病有关的组织特异性病理学。我们假设选择性， 保护性IRE 1/XBP 1 s或ATF 6信号传导的药理学激活代表了一种有希望的 治疗策略，以减轻衰老和许多与年龄有关的疾病的病理。来 在上一个资助期，我们利用基于细胞的表型高通量筛选（HTS）和全细胞 转录谱分析，以建立选择性激活适应性IRE 1/XBP 1的一流化合物 或ATF 6转录信号程序。这些化合物正在被我们的实验室和周围30多个实验室使用 定义药理学IRE 1/XBP 1或ATF 6的功能意义和治疗潜力 在年龄相关疾病中的活化，包括蛋白质错误折叠病症、缺血/再灌注损伤、眼 疾病、肥胖症-糖尿病、癌症和神经退行性疾病如阿尔茨海默病（AD）。在这里， 我们扩大这项研究，以建立下一代化合物，选择性地激活这些保护性的UPR， 途径，通过明确的作用机制，提高效价、疗效和药效学 和药代动力学特征，以增加其在不同实验和疾病模型中的应用。 此外，我们确定了这些化合物在衰老和AD小鼠模型中增强记忆的潜力， 揭示了通过药理学UPR激活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.