Endoplasmic reticulum stress and intestinal inflammation

项目总结/摘要 虽然未折叠蛋白反应（UPR）是内质网（ER）应激的结果， 肠上皮细胞（IEC）的分泌物被公认为促进炎症，但对肠上皮细胞（IEC）的分泌物知之甚少。 IEC衍生的UPR调节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进入组织或肠腔的传递， 反应或微生物群的组成。目前的研究建议涉及联合国- 回答了UPR如何介导免疫和微生物群功能相关因子的调节的问题 是重要的炎症性肠病（IBD），代谢综合征和肠道病原体的易感性。 我们的长期目标是解析出UPR介导的调控的具体机制和后果 参与免疫和微生物群功能的因素对这些（病理）生理活动很重要。这是... 本研究的目的是明确IEC相关的UPR如何导致无菌诱导， Thelper 17（TH 17）细胞在组织中的作用，或通过影响intelectin-1（ITLN 1）前体蛋白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obe中减少。 sity。我们的中心假设是，IEC相关的ER应激调节影响细胞增殖的因子的释放。 多种生理功能对免疫发育和微生物组的调节很重要。那个... 对我们提出的研究来说，发展对这些机制的深入了解将使我们的研究具有重要意义。 阐明IEC相关的ER应激在以下方面所起的作用， 通过控制白细胞介素-6和IEC衍生的ITLN 1作为危险因素的功能来调节TH 17细胞的发育 通过控制特定的微生物来治疗IBD和代谢综合征。我们的中心假设将被验证 有三个具体的目的：1）确定IEC ER应激在TH 17细胞的无菌诱导中的参与; 2） 确定IEC相关的ER应激如何影响微生物组的ITLN 1调节，以及; 3）表征所述对照， ITLN 1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 通过在ER中选择性表达葡萄糖调节蛋白78（GRP 78）抑制剂诱导ER应激 和其他模型，以揭示IEC中的UPR如何独立于 微生物群和在微生物TH 17诱导中发挥的作用。目标2将ITLN 1定义为UPR监管的IEC- 衍生的凝集素，其使用新开发的ITLN 1-Seq技术结合有限范围的致病菌， 这是如何调节结肠炎的诱发的。目标3将提供直接证据，证明ITLN 1对特定 微生物群将成为肥胖的致病因素。总的来说，这一提议意义重大，因为它将使我们能够 了解IEC相关的ER应激如何传播到组织或管腔中以调节宿主和/或 微生物群，分别，并提供新的层面，我们的理解几个非典型的活动， 与IEC相关的普遍定期审议的联系。

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.