Methods and approaches to expand the pharmacological toolset

项目总结 我们的实验室鉴定具有生理活性的小分子，以促进生物发现和 开发新药。R35早期调查员Mira提案的主要目标将是 我们的研究努力是共同的，我们相信，通过专注于三个关键领域，这将是最大限度的。在 首先，我们在再生医学领域一直在推进多种药理学方法。这里, 我们已经开发了一套独特的工具来促进再生组织修复，目标是河马YAP途径，如 以及多个组织驻留干细胞群体。我们将继续增强此工具集，描述 关于这些通路的信号逻辑的知识，并确定可能 在治疗上被利用，就像我们到目前为止所做的那样。其次，我们已经做出了重大努力，将粗略的 对细胞应激的二十种转录反应，包括热休克、氧化、蛋白平衡等。 我们已经开发出同类最好的NRF2途径激活剂，并已显示出临床应用的优越性。 动物模型中阶段性分子甲基巴多松龙。同样，我们使用化学工具来理解 关于中央碳代谢如何与细胞的氧化应激感应机制“对话”的基本语言。 我们将继续开发新的小分子来靶向这些基本上未连接的转录 回应。最后，我们将继续开发新的方法来有效地挖掘小型筛选文库 具有有趣和有用性质的分子。我们正在开发有效筛选文库的方法 新的共价反应基团以及开发新的方法来筛选酶家族。

Project summary Our laboratory identifies small molecules with physiological activity to advance biological discovery and to develop new medicines. The principal goal of this R35 early-stage investigator MIRA proposal will be to enable our research effort collectively, which we believe will be best maximized by focusing on three key areas. In the first, we have been advancing multiple pharmacological approaches in the field of regenerative medicine. Here, we have developed a unique toolset to promote regenerative tissue repair, targeting the Hippo YAP pathway as well as multiple tissue resident stem cell populations. We will continue to augment this toolset, delineating knowledge about the signaling logic of these pathways and identifying key mechanisms that can be potentially exploited therapeutically, as we have done to date. Second, we have significant efforts in ‘liganding’ the roughly twenty transcriptional responses to cellular stress, including heat shock, oxidative, proteostasis, among others. We have developed best in class activators of the NRF2 pathway and have shown superiority to the clinical stage molecule Bardoxolone methyl in animal models. Likewise, we have used chemical tools to understand the essential language of how central carbon metabolism ‘talks’ to the oxidative stress sensing machinery of the cell. We will continue to develop novel small molecules for targeting these largely unliganded transcriptional responses. Lastly, we will continue developing novel methods to effectively mine screening libraries for small molecules with interesting and useful properties. We are developing methods to effectively screen libraries for new covalent reactive groups as well as developing new methodology to screen enzyme families en masse.