Epithelial specific ubiquitination events

描述（由申请人提供）：胃肠道粘膜作为腔内内容物和底层组织间的界面，因此对维持粘膜稳态至关重要。肠道内容纳着数量庞大、分类多样的原核微生物群。在健康中，粘膜和微生物群在互利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群衍生的大分子（MAMPs）和宿主模式识别受体（PRRs）的存在介导的。PRRs激活已被充分研究的细胞内信号通路，使宿主细胞监测共生体并对病原体作出反应。在本研究中，我们将研究一种高度保守的信号通路Nrf2/ARE，它以监测外源性外源威胁而闻名，是一种对微生物群感知和反应的新颖而独特的系统。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的病理功能及其调节肠道内稳态的作用。Nrf2通路可能代表了宿主管理其共生微生物群的保守机制，并且它提供了一个有吸引力的治疗操作靶点。

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.