Endoplasmic reticulum stress and intestinal inflammation

内质网应激与肠道炎症

• 批准号: 9096752
• 负责人: Richard S Blumberg
• 金额: $ 64.77万
• 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 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9096752
• 关键词: Address; Affect; Attention; Autophagocytosis; B-Lymphocytes; Binding Proteins; Boxing; Cells; Cellular Structures; Coupled; Crohn' s disease; Dendritic Cells; Development; Diagnosis; Endoplasmic Reticulum; Epithelial; Epithelial Cells; Epithelium; Fees; Germ; Goals; Health; Homeostasis; Immune; Immune system; Immunoglobulin A; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Inflammatory disease of the intestine; Intestines; Label; Lead; Ligands; Light; Lymphoid Cell; Mediating; Metabolic; Mission; Molecular; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Neoplasms; Normalcy; Outcome; Paneth Cells; Pathogenesis; Pathway interactions; Physiological; Plasma Cells; Play; Prevention; Property; Proteins; Public Health; Research; Research Proposals; Role; Stress; Testing; Up-Regulation; Variant; Work; arm; coping; endoplasmic reticulum stress; enteritis; fitness; genetic risk factor; germ free condition; insight; intestinal crypt; intestinal epithelium; laser capture microdissection; member; microbial; microbiota; novel therapeutic intervention; personalized approach; prevent; protein misfolding; response; stem cell niche; transcriptome sequencing

 DESCRIPTION (provided by applicant): The highly secretory intestinal epithelial cell (IEC), in general, and Paneth cell (Pc), in particular, are exquisitely sensitive to endoplasmic reticulum (ER) stress due to unfolded and misfolded proteins and depend upon the unfolded protein response (UPR) and highly integrated pathway of UPR-regulated autophagy, to maintain homeostasis and avoid spontaneous enteritis and epithelial derived neoplasia due to disturbances in the intestinal stem cell (ISC) niche. The current research proposal addresses the unanswered question of how disturbances of the UPR and autophagy through an examination of X box binding protein 1 (XBP1) and autophagy related 16-like 1 protein (ATG16L1), respectively, result in epithelial abnormalities and spontaneous enteritis. Our long-term goals are therefore to parse out the specific consequences of and molecular pathways involved in IEC-derived, ER stress and autophagy associated enteritis. The objectives of the proposed studies are therefore to better elucidate how such enteritis emerges and the specific roles played by the innate and adaptive arms of the immune system in mediating IEC initiated intestinal inflammation, understand how ER stress and diminished autophagy in the Pc results in a specific crypt-associated expansion of enteroendocine (EE) cells and illuminate an unforeseen potential role of intelectin-1 in IEC centered, ER stress-induced intestinal inflammation. Our central hypothesis is that unresolved ER stress in the IEC, and especially the Pc, that is de- rived from a genetically-imposed inability of the UPR and autophagy to cope with physiologic (e.g. the com- mensal microbiota) and/or pathophysiologic (environmental) demands results in numerous primary epithelial disturbances. The rationale for these studies is that ER stress in IECs affects the Pc-ISC niche and are sensed by the immune system. Our central hypothesis will be tested by the following three specific aims: 1) define the role of the immune system in responding to ER stressed epithelium; 2) elucidate ER stress and autophagy interactions in the Pc-ISC niche, and; 3) determine the function of intelectin-1 in mediating the consequences of XBP1-deficiency in the Pc. In Aim 1, we will seek to understand the mechanisms by which group 1 innate like lymphoid cells sense natural-killer group 2 member D ligands on ER stressed IEC and induce enteritis and identify the microbial and epithelial factors that trigger dendritic cells to induce protective IgA+ plasma cells and mechanisms involved. In Aim 2, we will determine whether ATG16L1 compensates for and prevents spontaneous enteritis in XBP1-deficient Pc and how Pc associated ER stress disturbs the ISC niche and the role played by autophagy. Aim 3 will ascertain whether a metabolic disturbance represents a fundamental property of the XBP1-deficient epithelium and the role of intelectin-1 in these metabolic and inflammatory disturbances. Over- all this proposal is significant because it will further define the mechanisms by which the UPR and autophagy regulate IEC and Pc homeostasis which we predict will lead to highly precise means to define specific sub- types of IBD and facilitate new therapeutic approaches that are fine-tuned to a molecularly defined pathway.

 描述（申请人提供）：高度分泌的肠上皮细胞（IEC），一般来说，特别是潘氏细胞（Pc），对由于未折叠和错误折叠蛋白引起的内质网（ER）应激非常敏感，并且依赖于未折叠蛋白反应（UPR）和UPR调节的自噬的高度整合途径，以维持体内平衡并避免由于肠干细胞（ISC）小生境中的紊乱而引起的自发性肠炎和上皮源性瘤形成。目前的研究建议解决了未回答的问题，即通过检查X盒结合蛋白1（XBP 1）和自噬相关的16-like 1蛋白（ATG 16 L1），分别如何干扰UPR和自噬，导致上皮异常和自发性肠炎。因此，我们的长期目标是解析出IEC衍生的，ER应激和自噬相关肠炎的具体后果和分子途径。因此，所提出的研究的目的是更好地阐明这种肠炎如何出现以及免疫系统的先天和适应性臂在介导IEC引发的肠道炎症中所起的特定作用，了解Pc中的ER应激和减少的自噬如何导致肠内分泌（EE）细胞的特定隐窝相关扩增，并阐明intelectin-1在IEC中心，ER应激诱导的肠道炎症。我们的中心假设是IEC中未解决的ER应激，特别是Pc，其源自遗传上施加的UPR和自噬不能科普生理（例如共生微生物群）和/或病理生理（环境）需求，导致许多原发性上皮紊乱。这些研究的基本原理是IEC中的ER应激影响Pc-ISC生态位并被免疫系统感知。我们的中心假设将通过以下三个具体目标进行测试：1）定义免疫系统在响应ER应激上皮中的作用; 2）阐明Pc-ISC小生境中的ER应激和自噬相互作用;以及3）确定intelectin-1在介导Pc中XBP 1缺陷的后果中的功能。在目的1中，我们将试图了解机制，其中1组先天性淋巴样细胞的感觉自然杀伤细胞2组成员的D配体ER强调IEC和诱导肠炎，并确定微生物和上皮细胞因子，触发树突状细胞诱导保护性伊加+浆细胞和相关机制。在目标2中，我们将确定ATG 16 L1是否补偿和预防XBP 1缺陷Pc中的自发性肠炎，以及Pc相关的ER应激如何干扰ISC生态位和自噬所起的作用。目的3将确定代谢紊乱是否代表了XBP 1缺陷上皮的基本特性以及intelectin-1在这些代谢和炎症紊乱中的作用。总的来说，这个提议是重要的，因为它将进一步定义UPR和自噬调节IEC和Pc稳态的机制，我们预测这将导致高度精确的手段来定义IBD的特定亚型，并促进新的治疗方法，这些方法被微调到分子定义的途径。