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，研究先天免疫的进化保守机制。该研究项目将在麻省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。该候选人接受过传染病方面的培训，之前完成了生物化学方面的研究生培训。拟议的研究职业发展计划将为候选人提供遗传分析方面的培训，这是一个新的研究领域，为成为一名独立的内科科学家做准备，研究遗传易感生物秀丽隐杆线虫的先天免疫进化保守机制。哺乳动物的先天免疫系统是抵御病原体的第一道防线，在识别病原体和招募适应性免疫系统中发挥着核心作用。先天免疫通路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表明，人类先天免疫系统的关键要素在进化上是保守的。最近，该候选人与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。该候选人打算使用微阵列基因表达分析、RNAi功能基因组分析和正向基因抑制筛选相结合的方法，对秀丽隐杆线虫免疫应答中涉及的p38和JNK MAP激酶信号通路进行遗传和功能基因组解剖。这一提议的基本假设是，秀丽隐杆线虫免疫的研究将揭示进化保守的先天防御病原体攻击的机制。

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.