Defining non-transcriptional innate immune responses to bacterial endotoxin

定义对细菌内毒素的非转录先天免疫反应

• 批准号: 8660126
• 负责人: JONATHAN C KAGAN
• 金额: $ 41.13万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-16 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8660126
• 关键词: Applications Grants; Autophagocytosis; Bacteria; Binding; CD14 gene; Cessation of life; Data; Detection; Drug Design; Endocytosis; Endocytosis Pathway; Endosomes; Endotoxins; Extracellular Space; Goals; ITAM; Immune response; Immunity; Infection; Laboratories; Lead; Life; Lipopolysaccharides; Lymphocyte Antigen 96; Mediating; Membrane; Microbe; Motion; Pasteurella pseudotuberculosis; Pathway interactions; Phagocytosis; Process; Protein Tyrosine Kinase; Proteins; Research Proposals; Role; Second Messenger Systems; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Structure; Tissues; Transcriptional Regulation; Tyrosine Phosphorylation; Work; Yersinia; base; cell type; extracellular; immune activation; insight; lipopolysaccharide-binding protein; macrophage; microbial; novel; pathogen; receptor; response; second messenger; toll-like receptor 4

DESCRIPTION (provided by applicant): The goal of this proposal is to define a novel signal transduction pathway that is activated by bacterial lipopolysaccharide (LPS), but does not require signaling by Toll-like Receptor 4 (TLR4). While TLR4 is widely recognized to control transcriptional responses to LPS, its role in controlling immediate (non-transcriptional) responses is less clear. Examples of such responses include endocytosis, phagocytosis, autophagy and tyrosine phosphorylation. How LPS triggers these activities is largely unknown, but we have discovered that non-transcriptional responses control the classically-defined transcriptional responses to LPS. Understanding how microbial products activate distinct signal transduction pathways may permit the design of drugs that can target a subset of pathways therapeutically. Our proposal is founded on our recent discovery that LPS-induces the endocytosis of TLR4 by a process that does not require TLR4 signaling. Rather TLR4 is cargo for an endocytosis pathway that is activated by the LPS-binding protein CD14. While TLR4 does not direct its own endocytosis, this process is essential for TLR4 to induce TRIF-dependent signal transduction from endosomes. Our discovery of a response to LPS that does not require TLR4 signaling is important, as this receptor is thought to mediate all responses to LPS (also known as endotoxin). In this grant application, we propose to 1) identify new cytosolic regulators of CD14-dependent endocytosis, 2) identify the extracellular interactions that are needed for CD14-dependent endocytosis, and 3) identify the importance of CD14-dependent endocytosis in encounters between macrophages and pathogenic Yersinia. Collectively, this work will provide important insight into the means by which non-transcriptional responses to LPS are controlled.

描述（由申请人提供）：本提案的目的是定义一种新的信号转导途径，该途径由细菌脂多糖（LPS）激活，但不需要Toll样受体4（TLR4）的信号传导。虽然TLR4被广泛认为控制对LPS的转录反应，但其在控制即时（非转录）反应中的作用尚不清楚。此类反应的实例包括内吞作用、吞噬作用、自噬和酪氨酸磷酸化。LPS如何触发这些活动在很大程度上是未知的，但我们已经发现，非转录反应控制经典定义的LPS转录反应。了解微生物产品如何激活不同的信号转导途径可能允许设计药物，可以靶向治疗途径的子集。我们的建议是建立在我们最近的发现，LPS诱导TLR4的内吞作用的过程中，不需要TLR4信号。相反，TLR4是内吞途径的货物，其被LPS结合蛋白CD14激活。虽然TLR4不指导其自身的内吞作用，但该过程对于TLR4诱导来自内体的TRIF依赖性信号转导是必需的。我们发现对LPS的反应不需要TLR4信号传导是重要的，因为这种受体被认为介导对LPS（也称为内毒素）的所有反应。在这项授权申请中，我们提出1）确定新的CD14依赖性内吞作用的胞质调节剂，2）确定CD14依赖性内吞作用所需的细胞外相互作用，3）确定CD14依赖性内吞作用在巨噬细胞和致病性耶尔森菌之间相遇的重要性。总的来说，这项工作将提供重要的洞察力的手段，其中非转录反应LPS的控制。