Epithelial specific ubiquitination events

上皮特异性泛素化事件

• 批准号: 8627106
• 负责人: Andrew S Neish
• 金额: $ 38.75万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8627106
• 关键词: Acute; Agonist; Animals; Antioxidants; Apoptosis; Attention; Attenuated; Bacteria; Biochemical; Cell Proliferation; Cells; Chemicals; Complex; Cysteine; Data; Development; Differentiation and Growth; Disease; Drosophila genus; Enteral; Enzymes; Epithelial; Epithelium; Event; Gastrointestinal tract structure; Generations; Genes; Genetic Transcription; Growth Factor; Health; Homeostasis; Housing; Human; Immune; Immune response; In Vitro; Inflammation; Inflammatory; Injury; Intestines; Knockout Mice; Life; Maintenance; Mammalian Cell; Mechanics; Mediating; Methods; Microbe; Midgut; Molecular; Monitor; Mucous Membrane; Mus; NF-kappa B; Organism; Oxidants; Oxidation-Reduction; Pathway interactions; Pattern recognition receptor; Perception; Phagocytes; Physiological; Physiology; Plants; Probiotics; Process; Publishing; Reaction; Reactive Oxygen Species; Regulation; Regulator Genes; Regulon; Reporting; Role; Second Messenger Systems; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Stress; System; Therapeutic; Tissues; Ubiquitin; Ubiquitination; Up-Regulation; Work; Xenobiotics; base; cell growth; cell type; commensal microbes; cytokine; fly; gastrointestinal; germ free condition; in vivo; intestinal epithelium; intestinal homeostasis; macromolecule; microbial; mouse model; multicatalytic endopeptidase complex; mutant; new therapeutic target; novel; pathogen; pathogenic bacteria; response; second messenger; small molecule; therapeutic target

DESCRIPTION (provided by applicant): The gastrointestinal mucosa functions as an interface between luminal contents and underlying tissue compartments, and is thus vital in maintaining mucosal homeostasis. The gut lumen houses a numerically vast and taxonomically diverse prokaryotic microbiota. In health, the mucosa and microbiota thrive in a mutually beneficial symbiotic arrangement. Both host and microbe have evolved a complex system of mutual perception, response and reaction. This is mediated in part by the presence of microbiota derived macromolecules (MAMPs), and host pattern recognition receptors (PRRs) to respond to them. PRRs activate well studied intra cellular signaling pathways that allow the host cell to monitor commensals and react to pathogens. In this proposal we will study a highly conserved signaling pathway, Nrf2/ARE, well known for its role in monitoring exogenous xenobiotic threats, as a novel and distinct system for the perception and response to the microbiota. We will employ in vivo methods including genetically modified mice and Drosophila to study microbial activation of this pathway, evaluate the genes induced, and characterize the functional effects on gut survival, differentiation and proliferation. Our overall objectives are to define the pathobiologic function of microbially stimulated Nrf2 and its role regulating intestinal homeostasis. The Nrf2 pathway likely represents a conserved mechanism by which the host manages its commensal microbiota, and it presents an attractive target for therapeutic manipulation.

描述（由申请人提供）：胃肠粘膜充当管腔内容物和下面的组织区室之间的界面，因此对于维持粘膜稳态至关重要。肠腔内含有数量庞大且分类多样的原核微生物群。在健康方面，粘膜和微生物群在互利共生的情况下蓬勃发展。宿主和微生物都进化出了一个相互感知、反应和反应的复杂系统。这在一定程度上是由微生物衍生的大分子 (MAMP) 和对其做出反应的宿主模式识别受体 (PRR) 的存在介导的。 PRR 激活经过充分研究的细胞内信号传导途径，使宿主细胞能够监测共生体并对病原体做出反应。在本提案中，我们将研究高度保守的信号通路 Nrf2/ARE，它以其在监测外源性外源性威胁中的作用而闻名，作为一种新颖且独特的微生物群感知和响应系统。我们将采用包括转基因小鼠和果蝇在内的体内方法来研究该途径的微生物激活，评估诱导的基因，并表征对肠道存活、分化和增殖的功能影响。我们的总体目标是确定微生物刺激的 Nrf2 的病理生物学功能及其调节肠道稳态的作用。 Nrf2 途径可能代表了宿主管理其共生微生物群的保守机制，并且它为治疗操作提供了一个有吸引力的目标。