Endoplasmic reticulum stress and intestinal inflammation

项目摘要/摘要 尽管内质网(ER)应激引起的未折叠蛋白反应(UPR)- 来自肠上皮细胞(IEC)的ING被公认为促进炎症，但对其了解甚少 IEC衍生的普遍定期审议规范其他非规范功能的方式。最近，我们发现一个IEC- 相关的UPR可以调节影响免疫的因子向组织或肠腔的传递 响应或微生物区系的组成。目前的研究提案涉及联合国--联合国-- 回答了普遍定期审议如何调节涉及免疫和微生物区系功能的因素的问题 对炎症性肠病(IBD)、代谢综合征和对肠道病原体的易感性都很重要。 我们的长期目标是分析出普遍定期审议介导的监管的具体机制和后果 参与免疫和微生物区系功能的因素对这些(病理)生理活动很重要。妇产科医生- 这项研究的目的是明确定义IEC相关的UPR如何导致无菌诱导 组织中的TH17细胞或通过影响内毒素-1(ITLN1)前体来调节管腔微生物群。 诱导，一种活性鲜为人知的难以捉摸的微生物凝集素，在IBD中增加，在OBE中减少- 西迪丝。我们的中心假设是，IEC相关的内质网应激调节影响 对微生物群的免疫发育和调节很重要的各种生理功能。Ra- 我们提议的研究的理由是，对这些机制发展这样的见解将会释放出重要的 他们如何可能导致新的视角来阐明IEC相关的内质网应激在 IL-6和IEC衍生的ITLN1作为危险因子调控TH17细胞发育 通过特定微生物的控制来治疗IBD和代谢综合征。我们的核心假设将得到检验 有三个具体目标：1)明确IEC ER应激在TH17细胞不育诱导中的作用；2) 确定IEC相关的内质网应激如何影响微生物组的ITLN1调节；以及3)表征与IEC相关的内质网应激。 ITLN1缺陷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 葡萄糖调节蛋白78(GRP78)抑制剂在内质网选择性表达诱导内质网应激 和其他模型揭示了IEC中的UPR如何独立于 微生物区系及其在微生物TH17诱导中的作用。AIM 2将ITLN1定义为受普遍定期审议监管的IEC- 衍生凝集素，使用新开发的ITLN1-Seq技术与有限范围的病原体结合 这是如何调节结肠炎的诱导的。目标3将提供直接证据，证明ITLN1对特定的 微生物区系将成为肥胖的原因之一。总体而言，这项提议意义重大，因为它将使我们能够 了解IEC相关的内质网应激如何传播到组织或管腔来调节宿主和/或 微生物区系，为我们对几种非规范活动的理解提供了新的维度。 与IEC有关联的普遍定期审议的关系。

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.