p38-mediated defense pathway against pore-forming toxins

p38 介导的针对成孔毒素的防御途径

• 批准号: 7049641
• 负责人: RAFFI V AROIAN
• 金额: $ 28.29万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7049641
• 关键词: Caenorhabditis elegans; HeLa cells; RNA interference; bacterial toxins; double stranded RNA; enzyme activity; gene induction /repression; genetic screening; helminth genetics; host organism interaction; immune response; immunotoxicity; intracellular transport; mitogen activated protein kinase; phosphorylation; pore forming protein; western blottings

DESCRIPTION (provided by applicant): Pore-forming toxins (PFTs) are the single largest class of bacterial protein toxins known and are employed by many pathogenic bacteria (e.g., Staphylococcus aureus and Streptococcus pyogenes) to cause disease. These toxins punch holes in cell membranes and disrupt normal cell functions. Despite their importance, how PFTs work, how host cells respond to them, and whether or not animal cells have a defense against this form of attack are poorly understood. Recently, the nematode Caenorhabditis elegans has emerged as an excellent system for studying PFTs. Using C. elegans, it has been demonstrated that the p38 MAP kinase pathway is activated by PFT and that the p38 pathway provides an innate defense for the animal against attack by PFTs. Furthermore, the p38 pathway was subsequently shown to also protect mammalian cells against PFTs, suggesting this defense is conserved between C. elegans and mammals and expanding the known immunological functions of this key pathway. This grant proposes to follow up these results and utilize the powerful genomic and genetic tools of C. elegans to globally dissect what host genes are needed to activate the p38 MAPK pathway in response to PFT, to uncover the downstream targets of the p38 MAPK pathway that execute the defensive program, to study the role of these C. elegans p38 defense pathway genes in the defense of mammalian cells against PFT, and to study the physiological mechanisms by which the p38 pathway defends animal cells against PFT. Understanding how the p38 pathway controls defense against PFTs is likely to suggest new therapeutic strategies for dealing with a range of important bacterial pathogens that use PFTs as key virulence factors.

描述（由申请人提供）：成孔毒素（PFT）是已知的最大一类细菌蛋白质毒素，许多病原菌（例如金黄色葡萄球菌和化脓性链球菌）利用它来引起疾病。这些毒素会在细胞膜上穿孔并破坏正常的细胞功能。尽管 PFT 很重要，但人们对 PFT 的工作原理、宿主细胞如何对其做出反应以及动物细胞是否具有针对这种形式的攻击的防御能力知之甚少。最近，线虫秀丽隐杆线虫已成为研究 PFT 的优秀系统。使用秀丽隐杆线虫，已证明 p38 MAP 激酶途径是由 PFT 激活的，并且 p38 途径为动物提供了针对 PFT 攻击的先天防御。此外，p38 途径随后被证明还可以保护哺乳动物细胞免受 PFT 的侵害，这表明这种防御在秀丽隐杆线虫和哺乳动物之间是保守的，并扩展了该关键途径的已知免疫功能。该资助计划跟进这些结果，并利用线虫强大的基因组和遗传工具，全面剖析响应 PFT 激活 p38 MAPK 通路所需的宿主基因，以揭示 p38 MAPK 通路的下游靶标。执行防御程序，研究这些秀丽隐杆线虫p38防御途径基因在哺乳动物细胞防御PFT中的作用，并研究p38途径防御动物细胞免受PFT侵害的生理机制肺功能检查。了解 p38 通路如何控制对 PFT 的防御可能会提出新的治疗策略，用于处理一系列使用 PFT 作为关键毒力因子的重要细菌病原体。