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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)信号在调节先天免疫中起着关键作用，当解除调控时，还在炎症性疾病的发病机制中起重要作用。更好地理解分子机制调节TLR信号和炎症反应对提高疗效具有重要意义炎症性疾病的治疗方法。在之前的资助周期中，PI的实验室在这个领域有了开创性的发现。此外，我们已经产生了大量创新的初步这些数据为后续应用奠定了坚实的基础。特别是，我们的初步研究证明了蛋白激酶TBK1在控制TLR信号转导和预防炎症性疾病。尽管已知TBK1是一种介导I型干扰素(干扰素)诱导和在抗病毒先天免疫方面，由于缺乏可行的小鼠模型，对其体内功能的研究一直很少。利用新产生的TBK1条件基因敲除(CKO)小鼠，我们发现了TBK1在免疫和炎症反应的调节。我们的初步研究证明了一个关键的作用 Tbk1通过天然免疫细胞和肠上皮细胞共同作用来控制炎症反应细胞(IECS)。髓系细胞条件性TBK1 KO(TBK1-MKO)小鼠对结肠炎诱导和自发性地发生异常的脂肪组织扩张和炎症。TBK1对TLR的负性调节巨噬细胞中促炎症细胞因子的信号转导和TLR刺激表达。我们还有更多证明在IECS中有条件地删除TBK1会增加促炎细胞因子的产生和Th17 在肠道中产生细胞，使小鼠对肠道肿瘤的发生敏感。基于这些创新的发现，我们推测，TBK1在先天免疫细胞和IECS中都具有调节促炎性TLR的功能信号和炎症性疾病。本继续申请的总体目标是阐明 TBK1抗炎作用的机制。为了实现这一总体目标，我们将实现两个具体目标。在目标1中，我们将研究髓系细胞TBK1如何调节TLR信号和发炎。在目标2中，我们将阐明TBK1在IECS中调节肠道功能的机制免疫动态平衡与肿瘤发生。我们认为，这些拟议的研究涉及新的机制。调节TLR信号和炎症反应，并将导致高度影响的结果，基本上把场地向前推进。

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.