MicroRNA regulation of endothelial DNA repair to enhance anti-tumor immunity

项目摘要 内皮细胞在调节肿瘤微环境的多个方面发挥着重要作用。我们的实验室 已经确定miR-103是一种辐射诱导的miR，它会加剧DNA损伤，并具有整体肿瘤 临床前肿瘤模型中的抑制作用。我们还发现，这种miR的目标是DNA传感器3 优质核酸外切酶TREX1。这种酶在防止I型干扰素信号和 自身免疫激活。我们的初步研究表明，miR-103对TREX1的干扰会导致 肿瘤炎症的细胞和分子介质。在本提案中，我们将调查A)如何 肿瘤细胞中的MIR-103通路影响免疫微环境？B)有什么关系？ TREX1在血管系统DNA损伤依赖和非依赖信号传递中的作用 如何在体内遗传和靶向TREX1途径并利用一些由TREX1基因上调的途径 TREX1基因的中断。我们的研究将建立一种新的范式来激发强大的抗肿瘤免疫 MIR介导的DNA修复的破坏，增强了肿瘤微环境中的“危险信号”。

Project Summary Endothelial cells play an important role in regulating several aspects of the tumor microenvironment. Our lab has identified miR-103 as a radiation inducible miR that exacerbates DNA damage and has an overall tumor suppressive effect in preclinical tumor models. We also discovered that this miR targets a DNA sensor three prime exonuclease TREX1. This enzyme has important roles in preventing type I interferon signaling and autoimmune activation. Our pilot studies show that miR-103 disruption of TREX1 leads to an increase in cellular and molecular mediators of inflammation in tumors. In this proposal, we will investigate A) How this miR-103 pathway in the tumor cells affects the immune microenvironment? B) What are the relative contributions of TREX1 in DNA damage dependent and independent signaling in the vasculature and finally C) How to genetically and target TREX1 pathway in vivo and exploit some of the pathways upregulated by the disruption of TREX1. Our studies will establish a new paradigm to provoke potent anti-tumor immunity using miR-mediated disruption of DNA repair, which enhances `danger signals' in the tumor microenvironment.