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Studies of a new checkpoint regulator in the control of intestinal inflammation

控制肠道炎症的新检查点调节剂的研究

基本信息

批准号：
10621272
负责人：
Zhiqiang Zhang
金额：
$ 40.38万
依托单位：
METHODIST HOSPITAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-07 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10621272
关键词：
Address Antifungal Agents Autoimmunity Biological Assay Biological Response Modifiers Candida albicans Caspase Cell physiology Cells Chronic Colitis Colonic inflammation DNA Methylation DNA mapping Dendritic Cells Disease Environment Epigenetic Process Epithelial Cells Epithelium Family Family member Gastrointestinal tract structure Gene Expression Genes Homeostasis Host Defense Human Hyperactivity IL18 gene Immune Immune System Diseases Immune response Immunity Infection Inflammasome Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Innate Immune Response Innate Immune System Interleukin-1 Interleukin-1 beta Intestines Invaded Investigation Knockout Mice Lead Link Lupus Macrophage Mediating Modeling Modification Molecular Mucosal Immune System Mus Mycoses Natural Immunity Pathogenicity Pathway interactions Physiological Play Positioning Attribute Production Proteins RNA Virus Infections Receptor Signaling Respiratory System Role Scaffolding Protein Signal Transduction Site Stimulus Susceptibility Gene System T-Lymphocyte TRIM Family Testing Therapeutic Tissues Toll-like receptors Ubiquitination Work cell type chromatin modification cytokine fungus gain of function gastrointestinal gut inflammation histone modification immune activation in vivo innate immune function innate immune mechanisms insight intestinal epithelium loss of function microorganism mouse model multicatalytic endopeptidase complex novel novel strategies pathogen protein degradation response scaffold screening tool treatment strategy ubiquitin-protein ligase

项目摘要

Project Summary The innate immune system is the first line of host defense against invading pathogenic microorganisms. Innate immune cells can recognize these pathogens to induce cytokines against infections. However, this immune response must be tightly regulated to effectively eliminate invading microorganisms while minimizing tissue inflammation. Protein ubiquitination is important both in signal transduction and in proteasome-mediated protein degradation and is a pivotal regulatory mechanism for the innate immune system. A key component of the ubiquitination system is E3 ligase to specifically recognize the substrate for modification. We recently found that a TRIM family member, E3 ligase TRIM29, is highly expressed in intestinal epithelial cells (IECs). IECs act as a physical barrier between the external environment and the mucosal immune system. Importantly, after activation, IECs become innate immune-like cells to produce robust proinflammatory cytokines. We posit that TRIM29 is a key immune regulator to suppress innate immune response in a cell/tissue-specific manner to reduce intestinal inflammation. Notably, in the gut, genes encoding inflammasome components such as CARD9, NLRP3 and Caspases are associated with intestinal inflammation, and mice deficient in these genes are susceptible to colitis and fungal infection. However, hyperactive inflammasome signaling and uncontrolled IL-1 family cytokines lead to immune disorders and inflammatory disease. For instance, overproduction of inflammasome cytokine IL-18, excessive activation of NLRP3-inflammasome, or aberrant immune response to fungus play a major pathogenic role in colitis. Thus, this immune response must be finely tuned during immune activation for optimal protection against infections while avoiding unwanted inflammation. However, little is known about how such activation is terminated. Our preliminary studies show that TRIM29 negatively regulates IL-1 family cytokines produced by IECs during colitis or fungal infection. Moreover, expression of TRIM29 itself is significantly downregulated in inflamed colons, whereas production of IL-1 family cytokines is elevated. However, it is unknown whether lost expression of TRIM29 is regulated by IL-1 family cytokines and/or epigenetic modifications to control responses to environment stimuli in the intestines. We hypothesize that TRIM29 expression in IECs is a checkpoint regulator of IL-1 family cytokines crucial to reduce intestinal inflammation in colitis and fungal infection. We propose the following three aims to test this hypothesis: (1) To dissect molecular pathways that control TRIM29 expression in epithelial cells under normal and inflammatory conditions; (2) To define the mechanism by which TRIM29 inhibits IL-1 inflammation; (3) To investigate in vivo functions of TRIM29 in regulating IECs function in colitis and anti-fungal immunity.

项目摘要先天免疫系统是宿主抵御病原微生物入侵的第一道防线。先天免疫细胞可以识别这些病原体以诱导抗感染的细胞因子。然而，这种免疫反应必须严格调节，以有效地消除入侵的微生物，同时最大限度地减少组织炎症蛋白质泛素化在信号转导和蛋白酶体介导的蛋白质合成中具有重要作用它是天然免疫系统的关键调节机制。的关键组成部分泛素化系统是E3连接酶，以特异性识别底物进行修饰。我们最近发现， TRIM家族成员E3连接酶TRIM 29在肠上皮细胞（IEC）中高度表达。IEC作为外部环境和粘膜免疫系统之间的物理屏障。重要的是，激活后， IEC成为先天免疫样细胞，产生强大的促炎细胞因子。我们认为TRIM 29是一个以细胞/组织特异性方式抑制先天性免疫应答以减少肠炎症值得注意的是，在肠道中，编码炎性体组分如CARD 9、NLRP 3和NLRP 4的基因表达增加。半胱天冬酶与肠道炎症有关，缺乏这些基因的小鼠易患结肠炎和真菌感染。然而，过度活跃的炎性体信号传导和不受控制的IL-1家族细胞因子导致免疫紊乱和炎症性疾病。例如，炎性体细胞因子IL-18的过度产生， NLRP 3-炎性体的过度激活或对真菌的异常免疫应答是主要的致病因素结肠炎的作用因此，这种免疫反应必须在免疫激活过程中进行微调，以获得最佳保护防止感染，同时避免不必要的炎症。然而，很少有人知道这种激活是如何发生的。终止我们的初步研究表明，TRIM 29负调节IL-1家族细胞因子产生的结肠炎或真菌感染期间的IEC。此外，TRIM 29本身的表达在细胞中显著下调。炎症结肠，而IL-1家族细胞因子的产生升高。然而，不知是否失去了 TRIM 29的表达受IL-1家族细胞因子和/或表观遗传修饰的调节以控制应答肠道内的环境刺激。我们假设TRIM 29在IEC中的表达是一个检查点， IL-1家族细胞因子的调节剂，对减少结肠炎和真菌感染中的肠道炎症至关重要。我们提出了以下三个目标来验证这一假设：（1）解剖控制的分子途径， TRIM 29在正常和炎症状态下上皮细胞中的表达;（2）明确TRIM 29在炎症状态下的作用机制 TRIM 29抑制IL-1炎症反应的机制;（3）研究TRIM 29在体内对IEC的调节作用在结肠炎和抗真菌免疫中的作用。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

TRIM56 coiled-coil domain structure provides insights into its E3 ligase functions.

DOI：
10.1016/j.csbj.2023.04.022
发表时间：
2023
期刊：
COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL
影响因子：
6
作者：
Lou, Xiaohua;Ma, Binbin;Zhuang, Yuan;Xiao, Xiang;Minze, Laurie J.;Xing, Junji;Zhang, Zhiqiang;Li, Xian C.
通讯作者：
Li, Xian C.

DHX15 is required to control RNA virus-induced intestinal inflammation.