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

• 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
• 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

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.

项目摘要 内皮细胞在调节肿瘤微环境的几个方面发挥重要作用。我们实验室 已经将miR-103鉴定为放射诱导的miR，其加剧DNA损伤并具有整体肿瘤 在临床前肿瘤模型中的抑制作用。我们还发现，这种miR靶向DNA传感器3， 引物核酸外切酶TREX 1。这种酶在阻止I型干扰素信号传导中具有重要作用， 自身免疫激活我们的初步研究表明，miR-103对TREX 1的破坏会导致TREX 1表达的增加。 肿瘤中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）什么是相对的 TREX 1在血管系统中DNA损伤依赖性和非依赖性信号传导中的贡献，以及最后C） 如何在体内遗传和靶向TREX 1通路，并利用一些由TREX 1上调的通路， TREX 1的破坏。我们的研究将建立一个新的范式，以激发有效的抗肿瘤免疫， miR介导的DNA修复中断，增强了肿瘤微环境中的“危险信号”。