Endoplasmic reticulum stress and intestinal inflammation

内质网应激与肠道炎症

• 批准号: 8465875
• 负责人: Richard S Blumberg
• 金额: $ 51.14万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8465875
• 关键词: Affect; Animal Model; Autophagocytosis; Bacteria; Bacterial Antigens; Binding Proteins; Boxing; Cell Nucleus; Cell physiology; Cell secretion; Cells; Chemicals; Colitis; Crohn' s disease; Development; Disease susceptibility; Elements; Endoplasmic Reticulum; Endoribonucleases; Environmental Risk Factor; Enzymes; Epithelial; Epithelial Cells; Epithelium; Flagellin; Functional disorder; Genes; Genetic; Genetic Polymorphism; Goblet Cells; Human; Hypersensitivity; Immune; Immune response; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Inositol; Intestines; Lamina Propria; Listeria monocytogenes; Location; Lymphoid Cell; Mediating; Mediator of activation protein; Modeling; Molecular; Molecular Chaperones; Mus; Organ; Pancreas; Paneth Cells; Pathogenesis; Pathway interactions; Patients; Phosphotransferases; Play; Population; Predisposition; Prevention; Proteins; Reducing Agents; Reporting; Risk; Risk Factors; Role; Signal Pathway; Signal Transduction; Testing; Ulcerative Colitis; activating transcription factor; base; coping; endoplasmic reticulum stress; endoribonuclease; enteritis; genetic pedigree; member; microbial; microbiome; novel therapeutic intervention; pathogen; programs; public health relevance; response

DESCRIPTION (provided by applicant): Endoplasmic reticulum (ER) stress is an ancient conserved mechanism that allows cells, especially those with significant secretory function such as intestinal epithelial cells (IEC), to cope with the emergence of misfolded or unfolded proteins within the ER through a mechanism called the Unfolded Protein Response (UPR). The UPR consists of three ER-associated pathways that signal adaptive transcriptional programs within the nucleus. The most highly conserved pathway is that related to inositol requiring enzyme 1 (IRE1) which, through its endoribonuclease and kinase activities, regulates the transcriptional activity of X-box binding protein 1 (XBP1) and Jun related kinase (JNK), respectively. Deletion of the XBP1 gene specifically within IECs leads, uniquely, to spontaneous enteritis and sensitivity to colitis-inducing agents in association with increased ER stress, loss of Paneth and goblet cell function, an inability to manage luminal microbial challenges and a hypersensitivity of the IEC to signals emanating from bacterial and immune factors. XBP1 function with the IEC thus affects the two central determinants of IBD pathogenesis; the microbiota and immune response to the microbiota itself. Given that ER stress is readily demonstrable in animal models of inflammatory bowel disease (IBD) and the human condition and that the XBP1 gene harbors polymorphisms that confer risk for the development of IBD, it is reasonable to propose that the host's ability to manage ER stress within the IEC that is caused by environmental factors including inflammation itself is an important issue in understanding IBD pathogenesis. The current proposal aims to: (1) Elucidate the molecular pathways that connect unabated ER stress with inflammation that occurs in the presence of hypomorphic XBP1 function within the epithelium by characterizing the activity of the three major UPR pathways, the role NFkB activation, the potential intersection between ER stress and autophagy pathways, the effects of XBP1 deficiency on specific epithelial subtypes of epithelial cells and a determination of whether blockade of NFkB or JNK can ameliorate XBP1-related inflammation; (2) Define the inflammatory mediators derived from the epithelium that are involved in inflammation and their effects on mucosal immune cell populations by defining the role of TNFa and the characterization of the gut associated lymphoid cell populations in the intestines of XBP1-deficient mice, and; (3) Define the environmental factors involved in the exacerbation or alleviation of inflammation associated with XBP1- deficiency by characterizing the microbiome of XBP1-deficient mice and the role of the microbiota in inducing spontaneous enteritis and susceptibility to colitis and establishing whether agents that reduce ER stress can abrogate the intestinal inflammation arising from XBP1-deficient epithelia. These animal models and their interrogation provide a unique opportunity to identify and test novel therapeutic approaches for the treatment and prevention of IBD that may be generally extensible to IBD patients with a wide-range of phenotypic and genetic pedigrees.

描述（由申请人提供）：内质网（ER）应激是一种古老的保守机制，允许细胞，特别是那些具有显着分泌功能的细胞，例如肠上皮细胞（IEC），应对ER内错误折叠或未折叠蛋白质的出现通过一种称为未折叠蛋白反应（UPR）的机制。 UPR 由三个 ER 相关通路组成，这些通路向细胞核内的适应性转录程序发出信号。最高度保守的通路与肌醇需要酶 1 (IRE1) 相关，通过其内切核糖核酸酶和激酶活性，分别调节 X-box 结合蛋白 1 (XBP1) 和 Jun 相关激酶 (JNK) 的转录活性。 IEC 内 XBP1 基因的缺失会导致自发性肠炎和对结肠炎诱发剂的敏感性，并与内质网应激增加、潘氏细胞和杯状细胞功能丧失、无法管理管腔微生物挑战以及 IEC 过敏有关。来自细菌和免疫因素的信号。 XBP1 与 IEC 的功能因此影响 IBD 发病机制的两个核心决定因素；微生物群和对微生物群本身的免疫反应。鉴于 ER 应激在炎症性肠病 (IBD) 动物模型和人类状况中很容易得到证实，并且 XBP1 基因具有增加 IBD 发展风险的多态性，因此可以合理地提出宿主管理 ER 应激的能力在 IEC 中，由环境因素（包括炎症本身）引起的 IBD 是理解 IBD 发病机制的一个重要问题。目前的提案旨在：(1) 通过表征三个主要 UPR 途径的活性、NFkB 激活的作用、潜在的 XBP1 功能，阐明未减弱的 ER 应激与上皮内存在低效 XBP1 功能时发生的炎症之间的分子途径。 ER 应激和自噬途径之间的交叉、XBP1 缺陷对上皮细胞特定上皮亚型的影响以及确定 NFkB 或 JNK 的阻断是否可以改善XBP1相关炎症； (2) 通过定义 TNFa 的作用和 XBP1 缺陷小鼠肠道中肠道相关淋巴细胞群的特征，定义源自上皮的炎症介质，这些介质参与炎症及其对粘膜免疫细胞群的影响，以及; (3) 通过表征 XBP1 缺陷小鼠的微生物组和微生物群在诱导自发性肠炎和结肠炎易感性中的作用，确定与 XBP1 缺乏相关的炎症加剧或减轻所涉及的环境因素，并确定是否有降低 ER 的药物压力可以消除 XBP1 缺陷上皮细胞引起的肠道炎症。这些动物模型及其研究提供了一个独特的机会来识别和测试治疗和预防 IBD 的新治疗方法，这些方法通常可以扩展到具有广泛表型和遗传谱系的 IBD 患者。