Epithelial specific ubiquitination events

描述(由申请人提供)：胃肠道粘膜起着管腔内容物和底层组织间隔之间的接口作用，因此对维持粘膜内环境的稳定至关重要。肠腔内有数量巨大且分类多样的原核微生物区系。在健康方面，粘膜和微生物区系在互惠共生的安排下茁壮成长。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区系衍生的大分子(MAMP)和宿主模式识别受体(PRR)的存在来调节的。PRRs激活了研究得很好的细胞内信号通路，使宿主细胞能够监控共生体并对病原体做出反应。在这个建议中，我们将研究一个高度保守的信号通路，Nrf2/ARE，它在监测外源异生威胁方面的作用是众所周知的，作为一个新的和独特的系统来感知和响应微生物区系。我们将使用包括转基因小鼠和果蝇在内的体内方法来研究这一途径的微生物激活，评估诱导的基因，并表征其对肠道存活、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内环境平衡的作用。Nrf2途径可能代表了宿主管理其共生微生物区系的一种保守机制，并为治疗操作提供了一个有吸引力的靶点。 公共卫生相关性：人体肠道和肠道内正常的细菌微生物区系之间的关系在正常生理学和许多炎症和免疫相关疾病的发展中是重要的。这项提议将使用新的动物系统来研究宿主与共生细菌的相互作用，以确定这种串扰如何影响健康和疾病。

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. PUBLIC HEALTH RELEVANCE: The relationship of the human intestine and the normal bacterial microbiota within is important in normal physiology and in the development of numerous inflammatory and immune related diseases. This proposal will use novel animal systems to study the interaction of the host with commensal bacteria to determine how this cross talk influences health and disease.