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

MicroRNA调控内皮DNA修复增强抗肿瘤免疫

基本信息

批准号：
9914149
负责人：
Sudarshan Anand
金额：
$ 38.22万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-20 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9914149
关键词：
3-Dimensional Address Adjuvant Affect Aftercare Apoptotic Autoimmune Diseases Autoimmune Process B-Lymphocytes Biogenesis Biological Response Modifiers Blood Vessels Brain Neoplasms Breast Cancer Model Cell Cycle Arrest Cell Death Cell Line Cell Survival Cells Cessation of life Chemotherapy and/or radiation Coculture Techniques Colorectal Cancer Colorectal Neoplasms DNA DNA Damage DNA Double Strand Break DNA Repair Data Disease Endothelial Cells Endothelium Enzymes Exonuclease Genetic Growth Immune Immune response Immune system Immunologic Tests Immunomodulators Immunotherapy In Vitro Inflammation Inflammation Mediators Inflammatory Innate Immune System Interferon Type I Interferons Lysosomes Malignant Neoplasms Malignant neoplasm of lung Mediating MicroRNAs Modeling Molecular Mus Neoplasm Metastasis Neutrophilic Infiltrate Pathway interactions Patients Phenotype Pilot Projects Play Production Radiation Regulation Role Signal Transduction Small RNA Systemic Lupus Erythematosus TREX1 gene Testing Therapeutic Therapeutic Agents Three Prime Repair Exonuclease 1 Transferase Tumor Angiogenesis Tumor Immunity Vision Work angiogenesis anti-tumor immune response autocrine cancer therapy chemokine chimeric antigen receptor T cells cytokine ds-DNA endothelial dysfunction genome editing immune checkpoint blockade immune function immunogenic immunogenic cell death immunogenicity immunoregulation in vivo inhibitor/antagonist insight loss of function macrophage melanoma mouse model neoantigens neoplastic cell paracrine pre-clinical prevent radiation effect receptor response sensor spleen exonuclease targeted delivery tool tumor tumor growth tumor microenvironment tumor progression tumor-immune system interactions

项目摘要

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.

项目概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。我们的实验室已确定 miR-103 是一种辐射诱导型 miR，它会加剧 DNA 损伤并产生整体肿瘤临床前肿瘤模型中的抑制作用。我们还发现这个 miR 靶向 DNA 传感器三引发核酸外切酶 TREX1。该酶在阻止 I 型干扰素信号传导和自身免疫激活。我们的初步研究表明，miR-103 对 TREX1 的破坏会导致肿瘤炎症的细胞和分子介质。在本提案中，我们将研究 A）如何肿瘤细胞中的miR-103通路影响免疫微环境？ B）什么是亲戚 TREX1 在脉管系统中 DNA 损伤依赖性和独立信号传导中的贡献，最后 C) 如何在体内基因靶向 TREX1 通路并利用 TREX1 上调的一些通路 TREX1 的破坏。我们的研究将建立一个新的范例来激发有效的抗肿瘤免疫力 miR 介导的 DNA 修复破坏，增强了肿瘤微环境中的“危险信号”。