Molecular mechanisms regulating TLR signaling and inflammation

调节 TLR 信号传导和炎症的分子机制

基本信息

批准号：
10265710
负责人：
Shao-Cong Sun
金额：
$ 23.48万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-21 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10265710
关键词：
Address Adipose tissue Age Anti-Inflammatory Agents Antibodies Antiviral Agents ApcMin/+ mice Area Biological Response Modifiers Cells Colitis Coupled Data Disease Epithelial Cells Foundations Frequencies Funding Generations Genetic Homeostasis Host Defense Hypersensitivity Immune Immune response Immunologics In Vitro Infection Inflammation Inflammatory Inflammatory Response Interferon Type I Interleukin-17 Intestines Knock-out Knockout Mice Laboratories Lead Link MAP3K8 gene Mediating Mitogen-Activated Protein Kinases Molecular Mus Myeloid Cells Natural Immunity Obesity Pathogenesis Phenotype Phosphotransferases Play Positioning Attribute Production Protein Kinase Receptor Signaling Regulation Reporting Research Role Seminal Signal Induction Signal Transduction Solid TBK1 gene Therapeutic Tissue Expansion Toll-like receptors Ubiquitin base conditional knockout cytokine dextran sulfate sodium induced colitis experience immunoregulation improved in vivo innovation intestinal epithelium intestinal tumorigenesis macrophage mouse model novel prevent receptor-mediated signaling tumorigenesis

项目摘要

PROJECT SUMMARY/ABSTRACT Toll-like receptor (TLR) signaling plays a crucial role in mediating innate immunity and, when deregulated, also contributes to the pathogenesis of inflammatory diseases. Better understanding of the molecular mechanisms regulating TLR signaling and inflammatory responses is highly significant for improving the therapeutic approaches in the treatment of inflammatory diseases. During the previous funding cycles, the PI’s laboratory has made seminal discoveries in this area. Moreover, we have generated a large body of innovative preliminary data that form a solid foundation for this continuation application. In particular, our preliminary studies demonstrated a crucial role for the protein kinase, TBK1, in controlling TLR signaling and preventing inflammatory disorders. Although TBK1 is known as a kinase that mediates type I interferon (IFN) induction and antiviral innate immunity, its in vivo functions have been poorly studied due to the lack of a viable mouse model. Using newly generated TBK1 conditional knockout (cKO) mice, we have discovered novel functions of TBK1 in the regulation of immune and inflammatory responses. Our preliminary studies have demonstrated a crucial role for TBK1 in controlling inflammatory responses by functioning in both innate immune cells and intestinal epithelial cells (IECs). Myeloid cell-conditional TBK1 KO (Tbk1-MKO) mice are hypersensitive to colitis induction and spontaneously develop aberrant adipose tissue expansion and inflammation. TBK1 negatively regulates TLR signaling and TLR-stimulated expression of proinflammatory cytokines in macrophages. We have further demonstrated that conditional deletion of TBK1 in IECs increases proinflammatory cytokine production and Th17 cell generation in the intestine, sensitizing mice for intestinal tumorigenesis. Based on these innovative findings, we hypothesize that TBK1 functions in both innate immune cells and IECs to regulate proinflammatory TLR signaling and inflammatory disorders. The overall objective of this continuation application is to elucidate the mechanism underlying the anti-inflammatory functions of TBK1. To accomplish this overall objective, we will perform two specific aims. In Aim 1, we will examine how myeloid cell TBK1 regulates TLR signaling and inflammation. In Aim 2, we will elucidate the mechanism by which TBK1 functions in IECs to regulate intestinal immune homeostasis and tumorigenesis. We believe that these proposed studies address novel mechanisms that regulate TLR signaling and inflammatory responses and will lead to high-impact results that substantially advance the field.

项目摘要/摘要 Toll样受体（TLR）信号传导在介导先天免疫中起着至关重要的作用有助于炎症性疾病的发病机理。更好地理解分子机制调节TLR信号传导和炎症反应对于改善治疗非常重要治疗炎症性疾病的方法。在以前的资金周期中，PI的实验室在这方面发现了第二个发现。此外，我们产生了大量创新的初步为此持续应用构成坚实基础的数据。特别是我们的初步研究在控制TLR信号和防止的蛋白激酶TBK1中表现出至关重要的作用炎症性疾病。尽管TBK1被称为介导I型干扰素（IFN）诱导和抗病毒先天免疫，由于缺乏可行的小鼠模型，其体内功能的研究很差。使用新生成的TBK1条件敲除（CKO）小鼠，我们发现了TBK1的新功能免疫和炎症反应的调节。我们的初步研究表明了至关重要的作用对于TBK1，通过在先天免疫细胞和肠上皮中发挥作用来控制炎症反应细胞（IEC）。髓样细胞条件TBK1 KO（TBK1-MKO）小鼠对结肠炎诱导性不敏感自发发展异常的脂肪组织扩张和炎症。 TBK1负调节TLR 巨噬细胞中促炎细胞因子的信号传导和TLR刺激的表达。我们还有更多证明IEC中TBK1的条件缺失增加了促炎性细胞因子的产生和TH17 肠中的细胞产生，使小鼠对肠道肿瘤发生敏感。基于这些创新的发现，我们假设TBK1在先天免疫细胞和IEC中起作用以调节促炎性TLR 信号传导和炎症性疾病。该延续应用的总体目的是阐明 TBK1抗炎功能的基础机制。为了实现这一总体目标，我们将执行两个具体目标。在AIM 1中，我们将研究髓样细胞TBK1如何调节TLR信号传导和在AIM 2中，我们将阐明TBK1在IEC中发挥调节肠的机制免疫稳态和肿瘤发生。我们认为这些提出的研究涉及新的机制调节TLR信号传导和炎症反应，并将带来高影响的结果推进领域。

项目成果

期刊论文数量（19）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Peli1 negatively regulates type I interferon induction and antiviral immunity in the CNS.

DOI：
10.1186/s13578-015-0024-z
发表时间：
2015
期刊：
Cell & bioscience
影响因子：
7.5
作者：
Xiao Y;Jin J;Zou Q;Hu H;Cheng X;Sun SC
通讯作者：
Sun SC

Myeloid cell TBK1 restricts inflammatory responses.

DOI：
10.1073/pnas.2107742119
发表时间：
2022-01-25
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
Gao T;Liu T;Ko CJ;Zhang L;Joo D;Xie X;Zhu L;Li Y;Cheng X;Sun SC
通讯作者：
Sun SC

STAT3 restrains RANK- and TLR4-mediated signalling by suppressing expression of the E2 ubiquitin-conjugating enzyme Ubc13.

DOI：
10.1038/ncomms6798
发表时间：
2014-12-15
期刊：
NATURE COMMUNICATIONS
影响因子：
16.6
作者：
Zhang, Huiyuan;Hu, Hongbo;Greeley, Nathaniel;Jin, Jin;Matthews, Allison J.;Ohashi, Erika;Caetano, Mauricio S.;Li, Haiyan S.;Wu, Xuefeng;Mandal, Pijus K.;McMurray, John S.;Moghaddam, Seyed Javad;Sun, Shao-Cong;Watowich, Stephanie S.
通讯作者：
Watowich, Stephanie S.

New insights into NF-kappaB regulation and function.