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

• 批准号: 10271880
• 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
• 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/10271880
• 关键词: Address; Antifungal Agents; Autoimmunity; Biological Assay; Biological Response Modifiers; Candida albicans; Caspase; Cell physiology; Cells; Chronic; Colitis; DNA Methylation; DNA mapping; Dendritic Cells; Disease; Environment; Epigenetic Process; Epithelial; Epithelial Cells; Family; Family member; Gastrointestinal tract structure; Gene Expression; Genes; Homeostasis; Host Defense; Human; Hyperactivity; Immune; Immune System Diseases; Immune response; Immunity; Infection; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Innate Immune Response; Innate Immune System; Interleukin-1; Interleukin-1 beta; Interleukin-18; Intestines; Invaded; Investigation; Knockout Mice; Lead; Link; Lupus; 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; System; T-Lymphocyte; TRIM Family; Testing; Therapeutic; Tissues; Toll-like receptors; Ubiquitination; Work; cell type; chromatin modification; cytokine; fungus; gain of function; gastrointestinal; histone modification; immune activation; in vivo; inflammatory disease of the intestine; innate immune function; innate immune mechanisms; insight; intestinal epithelium; loss of function; macrophage; microorganism; mouse model; multicatalytic endopeptidase complex; novel; novel strategies; pathogen; protein degradation; response; scaffold; screening; tool; treatment strategy; ubiquitin-protein ligase

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 天然免疫系统是宿主抵御病原微生物入侵的第一道防线。先天的 免疫细胞可以识别这些病原体，从而诱导细胞因子对抗感染。然而，这种免疫力 必须严格控制反应，以有效消除入侵微生物，同时最大限度地减少组织 发炎。蛋白质泛素化在信号转导和蛋白酶体介导的蛋白质中都是重要的 降解，是先天免疫系统的关键调节机制。它的一个重要组成部分 泛素化系统是E3连接酶，用于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TRIM29在肠上皮细胞中高表达。IEC充当 外部环境和粘膜免疫系统之间的物理屏障。重要的是，在激活之后， IEC成为先天免疫样细胞，产生强大的促炎细胞因子。我们假设TRIM29是一个 关键免疫调节因子以细胞/组织特异性方式抑制先天免疫反应以减少肠道 发炎。值得注意的是，在肠道中，编码炎症体成分的基因，如CARD9、NLRP3和 半胱氨酸氨基转移酶与肠道炎症有关，缺乏这些基因的小鼠易患结肠炎。 和真菌感染。然而，过度活跃的炎症体信号和不受控制的IL-1家族细胞因子导致 免疫紊乱和炎症性疾病。例如，炎症体细胞因子IL-18的过度产生， NLRP3-炎症体的过度激活或对真菌的异常免疫反应是主要致病因素 在结肠炎中的作用。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，关于这种激活是如何进行的，人们知之甚少 被终止了。我们的初步研究表明，TRIM29对IL-1家族产生的细胞因子具有负面调节作用 结肠炎或真菌感染时出现IECS。此外，TRIM29本身的表达显著下调 结肠发炎，而IL-1家族细胞因子的产生增加。然而，目前还不清楚是否迷失了 TRIM29的表达受IL-1家族细胞因子和/或表观遗传修饰的调控 对肠道中的环境刺激。我们假设TRIM29在IECS中的表达是一个检查点 IL-1家族细胞因子的调节因子，对减少结肠炎和真菌感染的肠道炎症至关重要。 我们提出了以下三个目的来检验这一假说：(1)剖析调控的分子途径 TRIM29在正常和炎症状态下上皮细胞的表达；(2)明确其作用机制 TRIM29通过抑制IL-1炎症；(3)体内研究TRIM29对IECs的调节作用 在结肠炎和抗真菌免疫中的作用。