Mechanisms and Consequences of TLR Signal Transduction

TLR 信号转导的机制和后果

• 批准号: 6703217
• 负责人: Matthew J. Fenton
• 金额: $ 25.99万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6703217
• 关键词: biological signal transduction; cytokine; enzyme activity; enzyme linked immunosorbent assay; gene mutation; immunity; immunogenetics; intracellular; mitogen activated protein kinase; molecular cloning; nuclear factor kappa beta; phosphatidylinositol 3 kinase; protein kinase C; protein sequence; receptor expression; site directed mutagenesis; toll like receptor; transcription factor; western blottings

DESCRIPTION (provided by applicant): Mammalian Toll-like receptor (TLR) proteins are pattern recognition receptors for a diverse array of microbial products. Ten distinct TLR proteins have been identified, which appear to be non-redundant with respect to the ligands they recognize. Different TLR agonists induce distinct patterns of gene expression in macrophages and dendritic cells, suggesting that the innate immune system is capable of mounting a specific response to the pathogen being recognized. The mechanistic basis for this specificity depends on differences in signal transduction pathways activated by the various TLR proteins. TLR proteins play important roles in host defense at the levels of both innate and adaptive immunity in humans and other mammals. These receptors also play critical roles in the development of effective vaccines that protect against infection. Indeed, many of the most potent vaccine adjuvants currently know are TLR agonists. Immunization with a defined peptide antigen has been shown to elicit a Thl- and Th2-type immune response, depending on whether the antigen was administered in the presence of a TLR4 or a TLR2 agonist, respectively. Thus, the capacity of different TLR proteins to evoke distinct patterns of gene expression helps to define the precise nature of the immune response evoked during infection or vaccination. The overall objective of these proposed studies is to characterize the signal transduction pathways that lead to the distinct patterns of gene expression induced by different TLR agonists. Our specific aims will: (1) Define regions within the intracellular signaling domains of TLR3 and TLR4 that are necessary for the activation of NF-kappaB, MAP kinases, and cytokine expression. (2) Define regions within the intracellular signaling domains of TLR3 and TLR4 that are necessary for the activation of PKC-d and PI-3K. (3) Assess the mechanism of TLR tyrosine phosphorylation and its functional consequences.

描述(申请人提供)：哺乳动物Toll样受体(TLR)蛋白是多种微生物产品的模式识别受体。已经确定了10个不同的TLR蛋白，它们似乎相对于它们识别的配体是非冗余的。不同的TLR激动剂诱导巨噬细胞和树突状细胞表达不同的基因模式，表明天然免疫系统能够对被识别的病原体产生特定的反应。这种特异性的机制基础取决于不同TLR蛋白激活的信号转导途径的差异。在人类和其他哺乳动物的天然免疫和获得性免疫水平上，TLR蛋白在宿主防御中发挥着重要作用。这些受体在开发有效的预防感染的疫苗方面也发挥着关键作用。事实上，目前已知的许多最有效的疫苗佐剂都是TLR激动剂。已有研究表明，用确定的多肽抗原免疫可诱导Th1和Th2型免疫反应，这取决于该抗原是在TLR4激动剂还是TLR2激动剂存在的情况下给药。因此，不同TLR蛋白激发不同基因表达模式的能力有助于确定感染或疫苗接种过程中激发的免疫反应的确切性质。这些研究的总体目标是描述导致不同TLR激动剂诱导的不同基因表达模式的信号转导途径。我们的具体目标是： (1)确定TLR3和TLR4细胞内信号域中激活核因子-kappaB、MAP激酶和细胞因子所必需的区域。 (2)确定TLR3和TLR4细胞内信号域中激活PKC-d和PI-3K所必需的区域。 (3)探讨TLR酪氨酸磷酸化的机制及其功能后果。