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IRE1，未折叠蛋白反应(UPR)的关键调节因子，在调节肿瘤对缺氧和辐射的反应中所起的作用。我们已经完成了对120,000个化合物的高通量小分子筛选，并鉴定了几类LRE1抑制剂。我们和其他研究人员已经证明，LRE1内切酶活性是特异的，可以将XBP-1剪接成其活性形式，并且XBP-1的激活负责介导低氧和内质网应激下的存活。我们将开发针对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。我们还开发了一种XBP-1-荧光素酶转基因报告鼠，我们可以在其中跟踪Irel在肿瘤中的活性，以便优化我们的Irel抑制剂的给药程序。这些研究将在MMTV标记的乳腺癌模型和胰腺癌原位肿瘤模型中进行，因为这些肿瘤模型反映了更接近于人类癌症的肿瘤微环境的重要方面。此外，由于我们的数据显示，肿瘤微环境中的内质网应激可能调节辐射反应，我们将确定IREL在有氧和低氧细胞对辐射的辐射反应中的作用。这些研究将在Irel已被基因删除和抑制的肿瘤细胞系中进行，以及在Irel受到药物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，将IREL作为癌症治疗的靶点。

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.