Epithelial specific ubiquitination events

描述（由申请人提供）：胃肠道粘膜作为腔内容物和下层组织隔室之间的界面发挥作用，因此在维持粘膜稳态方面至关重要。肠腔容纳数量庞大且分类学上多样的原核微生物群。在健康方面，粘膜和微生物群在互利的共生安排中茁壮成长。宿主和微生物都进化出一个相互感知、反应和反应的复杂系统。这部分是由微生物群衍生的大分子（MAMP）和宿主模式识别受体（PRR）的存在介导的，以响应它们。PRR激活充分研究的细胞内信号传导途径，使宿主细胞能够监测病原体并对病原体作出反应。在这项提案中，我们将研究一个高度保守的信号通路，Nrf 2/ARE，众所周知，其在监测外源性外源性生物质威胁的作用，作为一个新的和独特的系统的感知和响应的微生物群。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活化，评估诱导的基因，并表征对肠道存活、分化和增殖的功能性影响。我们的总体目标是确定微生物刺激的Nrf 2的病理生物学功能及其调节肠道内稳态的作用。Nrf 2途径可能代表宿主管理其肠道微生物群的保守机制，并且它为治疗操作提供了有吸引力的靶标。

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.