Molecular Genetics of Innate Immunity in C. elegans

线虫先天免疫的分子遗传学

• 批准号: 8705535
• 负责人: Dennis H Kim
• 金额: $ 32.39万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8705535
• 关键词: Age; Aging; Attention; Behavioral; Caenorhabditis elegans; Data; Development; Drosophila genus; Endocrine; Environment; Evolution; Exposure to; Fluorescent in Situ Hybridization; Funding; G Protein-Coupled Receptor Signaling; G protein coupled receptor kinase; Gene Expression; Genes; Genetic; Genetic Determinism; Genetic Polymorphism; Genetic Screening; Glutamates; Goals; Grant; Hormonal; Hormones; Host Defense; Host Defense Mechanism; Human; Immune; Immune Tolerance; Immune response; Immunity; Infection; Intestines; Laboratories; Libraries; Light; Longevity; MAP Kinase Gene; MAPK14 gene; Mammals; Mediating; Methods; Microbe; Microbial Genetics; Molecular; Molecular Genetics; Natural Immunity; Nervous system structure; Neurons; Neurosecretory Systems; Nuclear; Octopamine; Organism; Output; Pathway interactions; Pattern; Physiological; Physiology; Process; Proteins; Pseudomonas aeruginosa; Receptor Activation; Regulation; Resistance; Role; Shapes; Signal Pathway; Signal Transduction; Testing; Universities; Work; age related; avoidance behavior; base; genetic analysis; immune activation; immune function; immunosenescence; insight; microbial; mutant; neurotransmitter release; pathogen; pathogenic bacteria; public health relevance; research study; response; sensory mechanism; single molecule

DESCRIPTION (provided by applicant): Evolutionary adaptation to environmental and endogenous microbes has shaped the immunity and physiology of multicellular organisms. Convergent genetic studies of innate immunity in mammals and in Drosophila revealed a commonality in the ancient signaling pathways of host defense, motivating me to embark on the molecular genetic analysis of innate immunity in the simple host organism Caenorhabditis elegans. The long-term goal of this project is to understand the molecular mechanisms of host defense in C. elegans, with the anticipation that studies in this simple host organism will shed light on conserved mechanisms of innate immunity and the evolution and physiology of host-microbe interactions. During the last funding period, we have continued to establish the mechanisms of innate immunity in C. elegans, while also extending our work to encompass the integrative physiology of host responses to infection. We discovered a physiological role for the Unfolded Protein Response in innate immune tolerance and defined how polymorphisms in neuronal genes can modulate the behavioral avoidance of pathogenic bacteria, underscoring the role of the nervous system in responses to microbes. We also initiated a study to understand the molecular basis of immunosenescence in C. elegans, the age-associated decline in immune function. Our studies of the C. elegans host have emphasized the influence that microbial pathogens and innate immune activation can have on host physiology. In this renewal application, we bring together a number of insights gained from these studies and turn our attention to how host-microbe interactions influence the physiology of aging and innate immunity. The basic underlying hypothesis of our proposal is that microbial pathogens can influence longevity and immunity of the C. elegans host through the modulation of neuroendocrine signaling pathways. Our preliminary studies have established a requirement for the TGF-ss signaling pathway in the neuroendocrine regulation of host defense. In addition, we observe marked pathogen-induced changes in host neuronal gene expression that we have defined quantitatively using single-molecule fluorescent in situ hybridization methods. We have three aims. First, we will define how the TGF-ss pathway promotes host defense against pathogenic bacteria and assess the role of this pathway during immunosenescence. Second, we will define the host sensory mechanisms involved in responding to changes in the microbial environment and inducing changes in neuronal TGF-ss expression. Third, we will identify the microbial molecule(s) and corresponding genetic determinants that modulate host physiology through changes in TGF-ss-dependent neuroendocrine signals. We anticipate that these studies will illuminate how the microbial environment of the host can modulate diverse aspects of physiology, including processes contributing to aging and longevity.

描述（由申请人提供）：对环境和内源性微生物的进化适应塑造了多细胞生物的免疫和生理。对哺乳动物和果蝇先天免疫的趋同遗传学研究揭示了宿主防御的古老信号通路的共同性，促使我开始对简单宿主生物秀丽隐杆线虫（Caesophylhabditis elegans）的先天免疫进行分子遗传学分析。本项目的长期目标是了解C. elegans，并期望在这种简单的宿主生物体中的研究将揭示先天免疫的保守机制以及宿主-微生物相互作用的进化和生理学。在上一个资助期内，我们继续建立了C.先天免疫的机制。线虫，同时也扩展了我们的工作，包括宿主对感染反应的综合生理学。我们发现了未折叠蛋白反应在先天免疫耐受中的生理作用，并定义了神经元基因的多态性如何调节对病原菌的行为回避，强调了神经系统在对微生物的反应中的作用。我们还启动了一项研究，以了解免疫衰老的分子基础，在C。与年龄相关的免疫功能下降。我们对C.线虫宿主强调微生物病原体和先天免疫激活对宿主生理的影响。在这个更新应用程序中，我们汇集了从这些研究中获得的许多见解，并将我们的注意力转向宿主-微生物相互作用如何影响衰老和先天免疫的生理学。我们提出的基本假设是微生物病原体可以影响C.线虫通过调节宿主的神经内分泌信号通路。我们的初步研究已经建立了在宿主防御的神经内分泌调节中对TGF-β信号通路的要求。此外，我们观察到显着的病原体诱导的宿主神经元基因表达的变化，我们已经定义了定量使用单分子荧光原位杂交方法。我们有三个目标。首先，我们将定义TGF-β途径如何促进宿主防御病原菌，并评估该途径在免疫衰老过程中的作用。其次，我们将定义宿主的感觉机制，参与响应微生物环境的变化，并诱导神经元TGF-β表达的变化。第三，我们将确定微生物分子和相应的遗传决定因素，通过TGF-β依赖性神经内分泌信号的变化来调节宿主生理。我们预计，这些研究将阐明宿主的微生物环境如何调节生理学的各个方面，包括有助于衰老和长寿的过程。