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.

项目概要/摘要 Toll 样受体 (TLR) 信号传导在介导先天免疫中发挥着至关重要的作用，并且当解除管制时，也有助于更好地了解炎症性疾病的分子机制。调节 TLR 信号传导和炎症反应对于改善治疗非常重要在之前的资助周期中，PI 的实验室研究了治疗炎症性疾病的方法。此外，我们在这一领域取得了开创性的发现，并产生了大量创新性的初步成果。数据为本次继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 信号传导和预防尽管 TBK1 被认为是介导 I 型干扰素 (IFN) 诱导和炎症性疾病的激酶。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少。使用新生成的 TBK1 条件敲除 (cKO) 小鼠，我们发现了 TBK1 在我们的初步研究已经证明了免疫和炎症反应的调节至关重要。 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骨髓细胞条件性 TBK1 KO (Tbk1-MKO) 小鼠对结肠炎诱导过敏。自发地发生异常的脂肪组织扩张和炎症。我们进一步了解了巨噬细胞中促炎细胞因子的信号传导和 TLR 刺激的表达。 IEC 中 TBK1 的条件性缺失会增加促炎细胞因子的产生和 Th17 基于这些创新发现，肠道细胞生成，使小鼠对肠道肿瘤发生敏感。我们研究 TBK1 在先天免疫细胞和 IEC 中发挥调节促炎性 TLR 的作用该继续申请的总体目标是阐明信号传导和炎症性疾病。 TBK1 抗炎功能的机制为了实现这一总体目标，我们将在目标 1 中，我们将研究骨髓细胞 TBK1 如何调节 TLR 信号传导和在目标 2 中，我们将阐明 TBK1 在 IEC 中调节肠道的机制。我们相信这些拟议的研究解决了新的机制。调节 TLR 信号传导和炎症反应，并将产生具有重大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）

Genetic rescue of lineage-balanced blood cell production reveals a crucial role for STAT3 antiinflammatory activity in hematopoiesis.

谱系平衡血细胞生成的基因拯救揭示了 STAT3 抗炎活性在造血过程中的关键作用。

DOI：
发表时间：
2018-03-06
期刊：
影响因子：
11.1
作者：
Zhang, Huiyuan;Li, Haiyan S;Hillmer, Emily J;Zhao, Yang;Chrisikos, Taylor T;Hu, Hongbo;Wu, Xiao;Thompson, Erika J;Clise;Millerchip, Karen A;Wei, Yue;Puebla;Kaushik, Saakshi;Santos, Margarida A;Wang, Bin;Garcia
通讯作者：
Garcia

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

Peli1 负向调节中枢神经系统中 I 型干扰素诱导和抗病毒免疫。

DOI：
发表时间：
2015
期刊：
影响因子：
0
作者：
Xiao, Yichuan;Jin, Jin;Zou, Qiang;Hu, Hongbo;Cheng, Xuhong;Sun, Shao
通讯作者：
Sun, Shao

IKKalpha, IKKbeta, and NEMO/IKKgamma are each required for the NF-kappa B-mediated inflammatory response program.

IKKalpha、IKKbeta 和 NEMO/IKKgamma 均是 NF-κ B 介导的炎症反应程序所必需的。

DOI：
发表时间：
2024-09-14
期刊：
The Journal of biological chemistry
影响因子：
0
作者：
Xiang Li;P. Massa;Adedayo Hanidu;G. W. Peet;Patrick Aro;Anne G. Savitt;S. Mische;Jun Li;K. Marcu
通讯作者：
K. Marcu

Immune receptor signaling: from ubiquitination to NF-κB activation.

免疫受体信号传导：从泛素化到 NF-κB 激活。

DOI：
发表时间：
2012-03
期刊：
影响因子：
24.1
作者：
Sun; Shao
通讯作者：
Shao

Deubiquitinating enzyme CYLD negatively regulates RANK signaling and osteoclastogenesis in mice.

去泛素化酶 CYLD 负向调节小鼠的 RANK 信号传导和破骨细胞生成。

DOI：
10.1172/jci34257
发表时间：
2008-05-01
期刊：
The Journal of clinical investigation
影响因子：
0
作者：
W. Jin;Mikyoung Chang;E. Paul;Geetha R Babu;Andrew J. Lee;W. Reiley;Ato O. Wright;Minying Zhang
通讯作者：
Minying Zhang