Endoplasmic reticulum stress and intestinal inflammation

内质网应激与肠道炎症

• 批准号: 10379412
• 负责人: Richard S Blumberg
• 金额: $ 65.9万
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10379412
• 关键词: Address; Adhesions; Affect; Autophagocytosis; Bacteria; Bacteroides fragilis; Binding; Binding Proteins; Cell physiology; Cells; Clostridium difficile; Colitis; Development; Dimensions; Endoplasmic Reticulum; Epithelial; Epithelial Cells; Experimental Models; Fusobacterium; Geographic Locations; Goals; Homeostasis; Immune; Immune response; In Vitro; Inflammation; Inflammatory Bowel Diseases; Interleukin-6; Intestines; Lead; Lectin; Light; Mediating; Metabolic syndrome; Methods; Microbe; Mission; Modeling; Mucous Membrane; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Neoplasms; Obesity; Organism; Outcome; Paneth Cells; Pathway interactions; Physiological; Play; Predisposition; Production; Proteins; Public Health; Regulation; Research; Research Proposals; Risk; Risk Factors; Role; Sterility; Stress; Techniques; Testing; Therapeutic; Time; Tissues; endoplasmic reticulum stress; enteric infection; enteric pathogen; enteritis; genetic risk factor; glucose-regulated proteins; gut inflammation; in vivo; inhibitor; insight; intestinal epithelium; metabolic phenotype; microbial; microbiome; microbiota; novel; obesity treatment; pathobiont; release factor; response; selective expression; tool; transmission process; treatment strategy

PROJECT SUMMARY/ABSTRACT Although the unfolded protein response (UPR) as a consequence of endoplasmic reticulum (ER) stress emanat- ing from an intestinal epithelial cell (IEC) is well recognized to promote inflammation, little is known about the ways that an IEC-derived UPR regulates other non-canonical functions. Recently, we discovered that an IEC- associated UPR can regulate transmission of factors into the tissues or intestinal lumen that affect immune responses or the composition of the microbiota, respectively. The current research proposal addresses the un- answered question of how the UPR mediated regulation of factors involved in immune and microbiota function are important to inflammatory bowel disease (IBD), metabolic syndrome and susceptibility to enteropathogens. Our long-term goals are to parse out the specific mechanisms and consequences of UPR-mediated regulation of factors involved in immune and microbiota function important to these (patho)physiologic activities. The ob- jective of this research is to specifically define how an IEC-associated UPR can cause the sterile induction of Thelper17 (TH17) cells in tissues or regulate the luminal microbiome through affecting intelectin-1 (ITLN1) pro- duction, an elusive microbial lectin of poorly understood activity, that is increased in IBD and decreased in obe- sity. Our central hypothesis is that IEC-associated ER stress regulates the release of factors which affect a variety of physiologic functions important to immune development and regulation of the microbiome. The ra- tionale for our proposed research is that developing such insights into these mechanisms will shed important light on how they might lead to new perspectives on elucidating the role played by IEC-associated ER stress in regulating TH17 cell development through control of interleukin-6 and IEC-derived ITLN1 function as a risk factor for IBD and metabolic syndrome through the control of specific microbes. Our central hypothesis will be tested with three specific aims: 1) define the involvement of IEC ER stress in the sterile induction of TH17 cells; 2) identify how IEC-associated ER stress affects ITLN1 regulation of the microbiome, and; 3) characterize the con- sequences of ITLN1-deficiency on immunometabolic function. In Aim 1 we will use a newly developed model of ER stress induction through selective expression of a glucose-regulated protein 78 (GRP78) inhibitor in the ER and other models to reveal how a UPR in the IEC instructs intestinal TH17 cell development independently of microbiota and the role played in microbial TH17 induction. Aim 2 will define ITLN1 as a UPR-regulated, IEC- derived lectin which binds a limited range of pathobionts using a newly developed technique of ITLN1-Seq and how this regulates the induction of colitis. Aim 3 will provide direct evidence that ITLN1 regulation of specific microbiota will act as a causal factor in obesity. Overall, this proposal is significant because it will allow us to understand how IEC-associated ER stress broadcasts itself into the tissues or lumen to regulate the host and/or the microbiota, respectively, and provide new dimensions on our understanding of several non-canonical activi- ties of an IEC-associated UPR.

项目概要/摘要 尽管内质网 (ER) 应激导致的未折叠蛋白反应 (UPR) 众所周知，来自肠上皮细胞（IEC）的细菌会促进炎症，但人们对它知之甚少。 IEC 派生的 UPR 规范其他非规范功能的方式。最近，我们发现 IEC- 相关的 UPR 可以调节影响免疫的因子向组织或肠腔的传输 分别是微生物群的反应或组成。当前的研究提案解决了 回答了 UPR 如何介导调节涉及免疫和微生物功能的因素的问题 对于炎症性肠病 (IBD)、代谢综合征和肠道病原体易感性很重要。 我们的长期目标是解析 UPR 介导的监管的具体机制和后果 涉及免疫和微生物群功能的因素对这些（病理）生理活动很重要。 OB- 本研究的目的是具体定义 IEC 相关的 UPR 如何引起无菌诱导 组织中的 Thelper17 (TH17) 细胞或通过影响 intelectin-1 (ITLN1) 亲来调节管腔微生物组 诱导，一种难以捉摸的微生物凝集素，其活性知之甚少，在 IBD 中增加，在肥胖中减少 城市。我们的中心假设是与 IEC 相关的 ER 应激调节影响因子的释放 对免疫发育和微生物组调节很重要的各种生理功能。拉- 我们提出的研究的要点是，对这些机制进行深入的了解将揭示重要的 阐明它们如何可能带来新的视角来阐明与 IEC 相关的 ER 应激在 通过控制白细胞介素 6 和 IEC 衍生的 ITLN1 功能作为危险因素来调节 TH17 细胞发育 通过控制特定微生物来治疗 IBD 和代谢综合征。我们的中心假设将得到检验 具有三个具体目标：1）定义 IEC ER 应激在 TH17 细胞无菌诱导中的作用； 2） 确定 IEC 相关的 ER 应激如何影响 ITLN1 对微生物组的调节； 3）表征反面 ITLN1 缺陷序列对免疫代谢功能的影响。在目标 1 中，我们将使用新开发的模型 通过在 ER 中选择性表达葡萄糖调节蛋白 78 (GRP78) 抑制剂诱导 ER 应激 和其他模型来揭示 IEC 中的 UPR 如何独立于肠道 TH17 细胞发育 微生物群以及在微生物 TH17 诱导中发挥的作用。目标 2 将 ITLN1 定义为受 UPR 监管、IEC- 使用新开发的 ITLN1-Seq 技术衍生的凝集素，可结合有限范围的病原体 这如何调节结肠炎的诱发。目标 3 将提供直接证据，证明 ITLN1 监管特定 微生物群将成为肥胖的致病因素。总体而言，该提案意义重大，因为它将使我们能够 了解 IEC 相关的 ER 应力如何将自身传播到组织或管腔中以调节宿主和/或 微生物群，并为我们理解几种非典型活动提供了新的维度 IEC 相关的 UPR 的联系。