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Regulation of caspase-1 activation by IQGAP1 during bacterial infection

细菌感染过程中 IQGAP1 对 caspase-1 激活的调节

基本信息

批准号：
8908161
负责人：
Lawton K Chung
金额：
$ 3.27万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-27 至 2017-06-26
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8908161
关键词：
Bacteria Bacterial Infections Binding Bone Marrow Caspase Caspase-1 Cells Communicable Diseases Defect Dendritic Cells Detection Development Employee Strikes Ensure Flow Cytometry Goals Host Defense Host Defense Mechanism Host resistance IQ motif containing GTPase activating protein 1 Immune Immune response In Vitro Infection Infectious Diseases Research Invaded Lead Length Leucine-Rich Repeat Leukocytes Measures Mediating Molecular Mus Nucleotides Organ Survival Pasteurella pseudotuberculosis Process Protein Isoforms Proteins Regulation Retroviridae Role Salmonella Salmonella enterica Salmonella typhimurium Scaffolding Protein Signal Transduction Type III Secretion System Pathway Virulence Virulence Factors Yersinia Yersinia infections Yersinia pestis cell motility combat design in vitro activity in vivo insight macrophage mutant new therapeutic target novel novel therapeutics pathogen prevent protein complex public health relevance receptor response therapeutic development

项目摘要

DESCRIPTION (provided by applicant): Recognition of pathogens by host defenses and subsequent activation of caspase-1 is important to resolve bacterial infection. Despite this, pathogens have developed mechanisms to prevent activation of caspase-1 to ensure survival and replication. An example of such is the effector YopM, an important virulence determinant of pathogenic Yersinia. YopM inhibits activation of caspase-1, yet the molecular mechanisms underlying this process remain largely unknown. We recently identified the host scaffolding protein IQGAP1 as a novel binding partner of YopM and found IQGAP1 to be important for activation of caspase-1 in response to Yersinia infection. These findings suggest that YopM inhibits activation of caspase-1 through targeting of IQGAP1. Given the importance of caspase-1 activation for host protection, understanding how IQGAP1 regulates activation of caspase-1 along with how pathogens subvert this process could aid the development of therapeutic strategies to combat bacterial infections. To accomplish this goal, three aims have been developed. Aim 1 seeks to identify the role of IQGAP1 for host protection against Yersinia. Aim 2 will determine the molecular mechanism of how IQGAP1 regulates activation of caspase-1 and how YopM disrupts this process. Aim 3 focuses on the importance of IQGAP1 for activation of caspase-1 in response to Salmonella, which also possess an effector that targets IQGAP1. Accomplishing these aims will provide mechanistic insight on how IQGAP1 regulates activation of caspase-1 and will contribute to development of novel therapeutic strategies against infectious disease.

描述(由申请人提供)：宿主防御识别病原体并随后激活caspase-1对解决细菌感染非常重要。尽管如此，病原体已经开发出防止caspase-1激活的机制，以确保生存和复制。其中一个例子是效应子YopM，它是致病性耶尔森氏菌的一个重要毒力决定因素。YopM抑制caspase-1的激活，但这一过程背后的分子机制在很大程度上仍不清楚。我们最近鉴定了宿主支架蛋白IQGAP1是YopM的一个新的结合伙伴，并发现IQGAP1在激活caspase-1以响应耶尔森菌感染方面起重要作用。这些发现表明YopM通过靶向IQGAP1来抑制caspase-1的激活。鉴于caspase-1激活对宿主保护的重要性，了解IQGAP1如何调节caspase-1的激活以及病原体如何颠覆这一过程有助于制定抗击细菌感染的治疗策略。为了实现这一目标，制定了三个目标。目标1试图确定IQGAP1在宿主保护耶尔森氏菌中的作用。目的2将确定IQGAP1如何调节caspase-1的激活以及YopM如何干扰这一过程的分子机制。目的3重点研究IQGAP1在沙门氏菌激活caspase-1中的重要性，沙门氏菌也具有针对IQGAP1的效应器。实现这些目标将提供对IQGAP1如何调节caspase-1激活的机械性洞察，并将有助于开发针对传染病的新治疗策略。