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Mechanisms of Intestinal Inflammation - Associated Systemic Genotoxicity

肠道炎症的机制 - 相关的全身基因毒性

基本信息

批准号：
8535933
负责人：
JONATHAN BRAUN
金额：
$ 37.84万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-21 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8535933
关键词：
Adoptive Transfer Aftercare Antioxidants Autoimmune Diseases C57BL/6 Mouse Cells Chronic Colorectal Cancer DNA Damage Development Disease Distant Gene Targeting Hematologic Neoplasms Hepatobiliary Image Analysis Immunology In Vitro Incidence Inflammation Inflammation Mediators Inflammatory Inflammatory Bowel Diseases Inflammatory Response Inflammatory disease of the intestine Interleukin-12 Intestinal Cancer Laboratories Lead Leukocytes Link Lymphoid Tissue Lymphoma Malignant Neoplasms Mediating Mediator of activation protein Methods Mus Nitrogen Oxygen Patients Peripheral Population Prevention Production Protein Biosynthesis Research Risk Scheme Serum Signal Pathway Signal Transduction Small Intestinal Adenocarcinoma Solid T-Cell Lymphoma T-Lymphocyte TNF gene Testing Time Tissues Work cell injury cell type chemokine congenic cytokine experience genotoxicity granulocyte in vivo inhibitor/antagonist macrophage novel receptor research study synergism

项目摘要

DESCRIPTION (provided by applicant): Patients with inflammatory bowel disease (IBD) are known to be at increased risk for intestinal and colorectal cancer. Mechanisms of this inflammation to cancer sequence have since been extensively characterized. Less characterized, however, are the mechanisms involved in the development of extraintestinal manifestations of disease, including hematopoietic cancers such as non-Hodgkin's T-cell lymphomas, hepatobiliary cancers, and other solid cancers and autoimmune disorders. We have previously identified genotoxicity to peripheral leukocytes in mice with chronic intestinal inflammation. Systemic genotoxicity is there an important and previously unappreciated consequence of chronic intestinal inflammation, which over time may promote the development of extraintestinal disease. In this application, we propose to determine the long-term implications of and determine the mechanisms involved in intestinal inflammation-associated systemic DNA damage. The first aim will clarify genotoxic load to multiple cell types in lymphoid and non-lymphoid tissues during chronic intestinal inflammation, and then characterize the long-term pathological effects these may impose. Our second aim is a mechanistic aim in which we will determine the sufficiency of cytokines such as TNF-1 and IL-12 in inducing systemic genotoxicity in vivo and in inducing genotoxicity in vitro, and then identify potential signaling pathways downstream of the receptors involved in induction of intracellular RONS formation. Necessity of de novo protein synthesis post-cytokine treatment and the temporal scheme of intracellular ROS and DNA damage will be determined via imaging analysis and treatment with ROS scavengers. In our third and fourth aims, we will test the hypothesis that damaged leukocytes from the gut circulate into the periphery, and the hypothesis that a local inflammatory response in various distant tissues are responsible for systemic genotoxicity, respectively. Specific components of the inflammatory response in distant tissues that may be responsible for this effect will be tested via adoptive transfer of serum or leukocyte populations from Ly5.1 mice with chronic intestinal inflammation into congenic Ly5.2 mice, and testing for systemic genotoxicity in Ly5.2 cells. Together, these experiments should clarify the inflammatory mediators and target cell types that link intestinal inflammation with systemic genotoxicity.

描述（由申请人提供）：已知炎症性肠病（IBD）患者患肠道和结直肠癌的风险增加。这种炎症对癌症序列的机制已被广泛表征。然而，肠外疾病表现发展的机制尚不明确，包括造血癌症，如非霍奇金t细胞淋巴瘤、肝胆癌和其他实体癌症和自身免疫性疾病。我们之前已经确定了慢性肠道炎症小鼠外周白细胞的遗传毒性。系统性遗传毒性是慢性肠道炎症的一个重要且以前未被认识到的后果，随着时间的推移，它可能促进肠外疾病的发展。在这个应用中，我们建议确定肠道炎症相关的系统性DNA损伤的长期影响和机制。第一个目的是澄清慢性肠道炎症期间淋巴和非淋巴组织中多种细胞类型的基因毒性负荷，然后表征这些可能造成的长期病理影响。我们的第二个目标是一个机制目标，我们将确定细胞因子如TNF-1和IL-12在体内诱导系统性遗传毒性和体外诱导遗传毒性的充足性，然后确定参与诱导细胞内RONS形成的受体下游的潜在信号通路。细胞因子治疗后重新合成蛋白质的必要性以及细胞内ROS和DNA损伤的时间方案将通过成像分析和ROS清除剂治疗来确定。在我们的第三和第四个目标中，我们将分别验证从肠道循环到外周的受损白细胞的假设，以及各种远处组织的局部炎症反应导致系统性遗传毒性的假设。通过将患有慢性肠道炎症的Ly5.1小鼠的血清或白细胞群过代转移到先天性Ly5.2小鼠中，并测试Ly5.2细胞的系统性遗传毒性，可以测试远处组织中可能导致这种效应的炎症反应的特定成分。总之，这些实验应该澄清炎症介质和靶细胞类型，将肠道炎症与系统性遗传毒性联系起来。