Development of Inhibitors of Supressors of Innate Immune Responses

先天免疫反应抑制剂的抑制剂的开发

• 批准号: 7652135
• 负责人: Jenny P Ting
• 金额: $ 22.79万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-15 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7652135
• 关键词: Affect; Aloral; Appendix; Bacteria; Bacterial RNA; Binding; Calcium; Caspase; Cell Line; Cells; Complex; Development; Excision; Family; Family member; Flagellin; Future; Gene Family; Gene Targeting; Genus Mycobacterium; Immune response; Immunity; Infection; Inflammatory Response; Interleukin-10; Leucine; Ligands; Mass Spectrum Analysis; Mediator of activation protein; Membrane; Modeling; Molecular; Myelogenous; Names; Natural Immunity; Outcome; Pattern; Pattern Recognition; Pattern recognition receptor; Phosphotransferases; Proteins; Proteoglycan; Purines; RNA Interference; Range; Receptor Activation; Role; Signal Transduction; Site; Structure; TLR2 gene; TNF gene; TNF receptor-associated factor 2; TNF receptor-associated factor 6; TRAF2 gene; Toll-Like Receptor Pathway; Toll-like receptors; Two-Dimensional Gel Electrophoresis; U937 Cells; Vaccination; Viral; Virulence; Virulence Factors; Work; Yersinia; Yersinia pestis; cytokine; fungus; inhibitor/antagonist; interest; lipoarabinomannan; lipoteichoic acid; macrophage; marenostrin; novel; pathogen; purine; receptor; response; small molecule

The discovery of Toll-like receptors (TLRs)in mammalians cells has revolutionized the understanding of innate immunity. These molecules constitute pattern recognition membrane molecules that recognize pathogenic products, including LPS, flagellin, proteoglycan, lipoteichoic acid, mycobacterium LAM, double stranded RNA, and bacterial CpG. The range of products derived from gram positive and negative bacteria, mycobacterium, fungi and viral products all activate the TLR pathways. As a consequence of TLR activation, cytokines that can activate adaptive immunity are also produced, thus they serve as a bridge between innate and adaptive immunity. Despite the pivotal role of these receptors, their involvement in defense against select agent is less well defined. In this proposal, we plan to directly examine the roles of TLRs and its downstream regulators in defense against a select agent, Yersinia pestis. We will focus on known TLRs and their downstream regulators as well as a new downstream regulator that we recently identified, the Monarch-1 protein. Monarch-1 downregulates TLR responses, including NF-.B/AP-1 activation, and TNF-. response. Thus its constitutes a novel suppressor of the TLR response that is likely to affect mmunity against r_atural infection and vaccination. Accordingly, the Aims are (1) To produce cell ines lacking known and new molecules in the TLR pathway by the use of interference RNA (RNAi :echnology). We plan to generate monocytic U937 cells that are defective in Monarch-1 as well as selected TLRs and their downstream signals including TRAF2, IRAKs, MyD88, and Md-2. (2) To determine if the removal of the genes targeted in Aim 1 causes alterations in responses to cellular products from Y. pestis. (3) To further understand how Monarch-1 inhibits inflammatory responses by determining components of the Monarch-1 protein complex.

Toll样受体（TLR）在大肠杆菌细胞中的发现彻底改变了 了解先天免疫。这些分子构成模式识别膜 识别致病产物的分子，包括LPS、鞭毛蛋白、蛋白聚糖、脂磷壁 酸、分枝杆菌LAM、双链RNA和细菌CpG。衍生产品系列 来自革兰氏阳性和阴性细菌、分枝杆菌、真菌和病毒产物都激活 TLR通路。作为TLR激活的结果，可以激活适应性免疫的细胞因子 也会产生，因此它们是先天免疫和适应性免疫之间的桥梁。尽管 这些受体的关键作用，它们参与防御选择剂是不太好定义。 在这份提案中，我们计划直接研究TLR及其下游调控因子的作用 来抵御一种特定的病原体鼠疫耶尔森氏菌我们将关注已知的TLR及其 下游调节器以及我们最近发现的新下游调节器， Monarch-1蛋白。Monarch-1下调TLR反应，包括NF-.B/AP-1活化， TNF-α。反应因此，它构成了一种新的TLR反应抑制剂，可能影响 自然感染免疫和疫苗接种。因此，本发明的目的是（1）生产细胞 通过使用干扰RNA（RNAi）在TLR途径中缺乏已知和新分子的品系 ：Technology）。我们计划产生Monarch-1缺陷的单核细胞U937细胞， 选择的TLR及其下游信号，包括TRAF 2、IRAK、MyD 88和Md-2。(2)到 确定目标1中靶向基因的去除是否会导致细胞免疫反应的改变 Y的产品。鼠疫(3)为了进一步了解Monarch-1如何抑制炎症反应， 通过确定Monarch-1蛋白复合物的成分。