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）：形成孔的毒素（PFT）是已知的最大类细菌蛋白毒素类，并由许多致病性细菌（例如金黄色葡萄球菌和金葡萄球菌和pyogenes链球菌）使用。这些毒素在细胞膜中打孔并破坏正常细胞功能。尽管它们的重要性，PFT的工作原理，宿主细胞如何对其做出反应，以及动物细胞是否对这种攻击形式有所了解。最近，线虫秀丽隐杆线虫已成为研究PFT的绝佳系统。使用秀丽隐杆线虫，已经证明了p38 MAP激酶途径被PFT激活，并且p38途径为动物免受PFT的攻击提供了天生的防御。此外，随后证明了p38途径也可以保护哺乳动物细胞免受PFT的影响，这表明这种防御是在秀丽隐杆线虫和哺乳动物之间保守的，并扩展了该关键途径的已知免疫学功能。 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 p38途径捍卫动物细胞免受PFT的机制。了解p38途径如何控制对PFT的防御可能会提出新的治疗策略，以处理一系列使用PFT作为关键毒力因素的重要细菌病原体。