The Role of Ire1 in Modulating the Response of Tumors to Hypoxia and Radiation

在这个项目中，我们将研究Ire 1的作用，一个关键的调节未折叠蛋白反应（UPR），在调节肿瘤对缺氧和辐射的反应。我们已经完成了对> 120，000种化合物的高通量小分子筛选，并鉴定了几类lre 1抑制剂。我们和其他研究人员已经表明，lre 1核酸内切酶的活性是特定的剪接XBP-1到其活性形式和XBP-1的激活是负责介导缺氧和ER应激下的生存。我们将开发Irel特异性核酸内切酶活性的小分子抑制剂，作为乳腺癌和胰腺癌的治疗策略。我们还开发了XBP-1-荧光素酶转基因报告小鼠，其中我们可以跟踪肿瘤中的Irel活性，以优化我们的Irel抑制剂的给药方案。这些研究将在MMTV-Tag乳腺肿瘤模型以及胰腺癌原位肿瘤模型中进行，因为这些肿瘤模型反映了与人类癌症更相似的肿瘤微环境的重要方面。此外，由于我们的数据显示，ER压力在肿瘤微环境中可能会调节辐射反应，我们将确定Irel在有氧和缺氧细胞对辐射的辐射反应中的作用。这些研究将在其中Irel已被遗传删除抑制的肿瘤细胞系以及其中Irel被基因操纵的原位胰腺肿瘤中进行。这些数据将有助于确定Irel在肿瘤对缺氧和辐射的反应中的作用。这些知识将进一步发展分子策略，以靶向Irel用于癌症治疗。

In this project, we will investigate the role of Ire1, a critical regulator of the unfolded protein response (UPR), in modulating the tumor response to hypoxia and radiation. We have completed a high throughput small molecule screen of >120,000 compounds and identified several classes of lre1 inhibitors. We and other investigators have shown that lre1 endonuclease activity is specific for splicing XBP-1 into its active form and that XBP-1 activation is responsible for mediating survival under hypoxia and ER stress. We will develop small molecule inhibitors for Irel's specific endonuclease activity as a therapeutic strategy for breast and pancreatic cancer. We have also developed an XBP-1-luciferase transgenic reporter mouse in which we can follow Irel activity in tumors in order to optimize the dosing schedules of our Irel inhibitors. These studies will be conducted in an MMTV-Tag breast tumor model as well as a pancreatic cancer orthotopic tumor model as these tumor models reflect important aspects of the tumor microenvironment that more closely resembles human cancer. In addition, because of our data showing that ER stress within the tumor microenvironment may modulate radiation response, we will determine the role of Irel in the radiation response of aerobic and hypoxic cells to radiation. These studies will be performed in tumor cell lines in which Irel has been genetically deleted inhibited as well as in orthotopic pancreas tumors in which Irel is pharmacologically manipulated. These data will help to define the role of Irel in the response of tumors to hypoxia and radiation. This knowledge will further the development of molecular strategies to target Irel for cancer therapy.