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（由申请人提供）：一般来说，高度分泌性肠上皮细胞（IEC），特别是潘氏细胞（Pc），对由于未折叠和错误折叠蛋白质引起的内质网（ER）应激非常敏感，并且取决于未折叠蛋白反应（UPR）和 UPR 调节的自噬的高度整合途径，以维持稳态并避免由于目前的研究提案分别通过检查 X 盒结合蛋白 1 (XBP1) 和自噬相关 16-like 1 蛋白 (ATG16L1) 来解决 UPR 和自噬如何受到干扰这一尚未解答的问题。因此，我们的长期目标是解析 IEC 衍生的 ER 应激和自噬相关的具体后果和分子途径。因此，拟议研究的目的是更好地阐明这种肠炎是如何出现的，以及免疫系统的先天性和适应性臂在介导 IEC 引发的肠道炎症中所发挥的具体作用，了解 ER 应激和 PC 中自噬减少是如何产生的。在肠内分泌 (EE) 细胞的特定隐窝相关扩张中，阐明了 intelectin-1 在以 IEC 为中心的 ER 应激诱导的肠道炎症中不可预见的潜在作用。 IEC 中未解决的 ER 应激，尤其是 PC，是由于 UPR 和自噬无法应对生理（例如共生微生物群）和/或病理生理（环境）需求而导致的这些研究的基本原理是 IEC 中的 ER 应激会影响 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检验：1）定义免疫系统在应对 ER 应激上皮细胞中的作用；2）阐明 Pc-ISC 生态位中的 ER 应激和自噬相互作用；3）确定intelectin-1 在介导 PC 中 XBP1 缺陷的后果中的功能 在目标 1 中，我们将寻求了解第 1 组先天样淋巴细胞感知的机制。 ER 上的自然杀伤剂组 2 成员 D 配体应激 IEC 并诱发肠炎，并鉴定触发树突状细胞诱导保护性 IgA+ 浆细胞的微生物和上皮因子以及相关机制。在目标 2 中，我们将确定 ATG16L1 是否补偿和预防自发性。 XBP1 缺陷 PC 中的肠炎以及 Pc 相关的 ER 应激如何扰乱 ISC 生态位以及自噬所发挥的作用。确定代谢紊乱是否代表 XBP1 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，这一提议很重要，因为它将进一步定义 UPR 和自噬的调节机制。我们预测 IEC 和 Pc 稳态将带来高度精确的方法来定义 IBD 的特定亚型，并促进针对分子定义途径进行微调的新治疗方法。