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防御的第一线，以防止入侵致病性微生物。先天免疫细胞可以识别这些病原体可诱导细胞因子，以防止感染。但是，这种免疫必须严格调节反应，以有效消除入侵的微生物，同时最小化组织炎。蛋白质泛素化在信号转导和蛋白酶体介导的蛋白质中都很重要退化，是先天免疫系统的关键调节机制。一个关键组成部分泛素化系统是E3连接酶，可以专门识别用于修饰的底物。我们最近发现 Trim家族成员E3连接酶Trim29在肠上皮细胞（IEC）中高度表达。 iecs充当外部环境与粘膜免疫系统之间的物理障碍。重要的是，激活后， IEC成为先天免疫样细胞，产生鲁棒性促炎细胞因子。我们认为Trim29是关键免疫调节剂以细胞/组织特异性抑制先天免疫反应以减少肠道炎。值得注意的是，在肠道中，编码炎症组成分（例如card9，nlrp3和）的基因胱天蛋白酶与肠道炎症有关，这些基因缺乏的小鼠容易受到结肠炎的影响。和真菌感染。但是，多动激活的炎性体信号传导和不受控制的IL-1家族细胞因子铅免疫疾病和炎症性疾病。例如，炎性体细胞因子IL-18的过量生产，过度激活NLRP3-炎性症或对真菌的异常免疫反应发挥了主要的致病性在结肠炎中的作用。因此，必须在免疫激活期间对这种免疫反应进行细调，以获得最佳保护反对感染，同时避免不必要的炎症。但是，对于这种激活的方式知之甚少终止。我们的初步研究表明，TRIM29负调控IL-1家族细胞因子由结肠炎或真菌感染期间的IEC。此外，TRIM29本身的表达显着下调结肠发炎，而IL-1家族细胞因子的产生升高。但是，未知是否丢失了 TRIM29的表达受IL-1家族细胞因子和/或表观遗传修饰的调节，以控制反应到肠中的环境刺激。我们假设IEC中的TRIM29表达是一个检查点 IL-1家族细胞因子的调节剂对于减少结肠炎和真菌感染的肠炎至关重要。我们提出以下三个旨在检验这一假设的目的：（1）剖析控制的分子途径在正常和炎症条件下，TRIM29在上皮细胞中的表达；（2）定义机制 TRIM29抑制IL-1炎症；（3）调查调节IEC中TRIM29的体内功能结肠炎和抗真菌免疫的功能。

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.