Genetic analysis of innate immunity in C elegans

描述（由申请人提供）：本申请描述了一个为期五年的研究职业发展计划，在先天免疫的进化保守机制的研究。该研究计划将在马萨诸塞州总医院分子生物学系和哈佛医学院遗传学系的Frederick Ausubel教授的指导下进行。候选人接受过传染病方面的培训，以前完成过生物化学方面的研究生培训。 拟议的研究职业发展计划将提供遗传分析方面的培训，这是候选人的一个新的研究领域，为作为一名独立的医生-科学家的职业生涯做准备，研究遗传上易处理的生物体-秀丽隐杆线虫中先天免疫的进化保守机制。哺乳动物的先天免疫系统代表了抵抗病原体的第一道防线，在病原体的识别和适应性免疫系统的募集中起着核心作用。先天免疫途径的紊乱与感染性休克的发病机制有关。来自昆虫免疫研究的证据已经确定，人类先天免疫系统的关键要素在进化上是保守的。最近，候选人与Ausubel实验室的其他成员合作表明，线虫防御细菌病原体需要高度保守的p38 MAP激酶信号通路。该候选人打算对参与C.使用微阵列基因表达分析、具有RNAi的功能基因组分析和正向遗传抑制筛选的组合来检测线虫的免疫应答。这一建议的基本假设是，C。elegans免疫将揭示进化上保守的抵抗病原体攻击的先天防御机制。

DESCRIPTION (provided by applicant): This application describes a five-year research career development program in the study of evolutionarily conserved mechanisms of innate immunity. The research program will be conducted under the mentorship of Professor Frederick Ausubel in the Department of Molecular Biology, Massachusetts General Hospital, and the Department of Genetics, Harvard Medical School. The candidate is trained in Infectious Diseases and previously completed graduate training in biochemistry. The proposed research career development program will provide training in genetic analysis, a new field of research for the candidate, in preparation for a career as an independent physician-scientist studying evolutionarily conserved mechanisms of innate immunity in the genetically tractable organism, Caenorhabditis elegans. The mammalian innate immune system represents the first line of defense against pathogens, playing central roles in the recognition of pathogens and the recruitment of the adaptive immune system. Derangement of pathways of innate immunity is implicated in the pathogenesis of septic shock. Evidence from studies of insect immunity has established that critical elements of the human innate immune system are evolutionarily conserved. Recently, the candidate in collaboration with other members in the Ausubel laboratory has shown that a highly conserved p38 MAP kinase signaling pathway is required for the nematode defense against bacterial pathogens. The candidate intends to carry out a genetic and functional genomic dissection of the p38 and JNK MAP kinase signaling pathways involved in the C. elegans immune response using a combination of microarray gene expression analysis, functional genomic analysis with RNAi, and a forward genetic suppressor screen. The basic underlying hypothesis of this proposal is that the study of C. elegans immunity will reveal evolutionarily conserved mechanisms of innate defense against pathogen attack.