Administrative Supplement: Dissection of NF-kappaB regulation by the ubiquitin E3 ligase PDLIM2 in lung innate immunity and diseases

摘要 NF-κ B B在多种疾病如肺病的炎症和发病机制中起致因作用， 是美国第三大杀手，每七个人中就有一个死于这种疾病。然而，我们无法 由于其在生理学中同样重要的作用，特别是， 先天免疫和宿主防御分离NF-κ B B的这些功能将克服这一障碍， 这是对抗肺病和其他疾病的有力手段。尽管驱动NF-κ B B活化的核心机制 已经被很好地定义，并且在大多数生理和致病条件下是相同的， 生理性与致病性NF-κ B B的差异仍然很大程度上未知。最近，我们已经证明， NF-κ B B首次在正常和恶性肺上皮细胞中表现出不同的活化模式， 这是肺的第一道防线，也是先天免疫的关键组成部分。我曾透露， 也是第一次，含有PDZ-LIM结构域的蛋白质PDLIM 2作为肿瘤抑制因子和泛素E3 选择性降解NF-κ B B的“致病性”形式而非“生理性”形式（从而防止 病原体激活，同时允许炎症刺激对NF-κ B进行生理激活），并且可以靶向 作为人肺癌的真实小鼠模型中的单一或组合疗法。就像人类的肺癌， 值得注意的是，PDLIM 2在患有慢性阻塞性肺病（COPD）的患者的肺中被抑制， 间质性肺疾病（ILD），PDLIM 2抑制与疾病严重程度和患者不良反应有关。 生存肺上皮特异性或PDLIM 2的整体缺失使小鼠对自发性肺纤维化高度易感。 细菌内毒素脂多糖诱发肺癌和急性肺损伤死亡 （LPS）。基于这些开创性的发现，在本提案中，我们将确定PDLIM 2的功能伙伴 并确定它们作为泛素E3连接酶复合物的生化机制， 肺上皮细胞NF-κ B B的差异活化。我们还将确定在体内和体外的作用 以及这种调节在肺部疾病和宿主防御肺部感染中的分子机制， 条件性和诱导性敲除（KO）或敲入（KI）小鼠以及PDLIM 2和/或NF-κ B B的细胞。这些研究 将提高我们对正常肺生理和肺部疾病的理解，并开辟新的途径， 研究NF-κ B B调控及作用。它们还可能导致新的临床可行的方法，以选择性地靶向 致病性NF-κ B B，并揭示了更好的肺部疾病治疗的新的治疗靶点。

Abstract NF-B plays a causative role in the inflammation and pathogenesis of various diseases such as lung disease, the third leading killer in the United States responsible for one in seven deaths. However, we have been unable to successfully target it for clinical treatment due to its equally important roles in physiology, and in particular, innate immunity and host defense. Teasing apart these functions of NF-B will overcome this barrier resulting in a powerful means to fight lung and other diseases. Although the core mechanism driving NF-B activation has been well defined and is the same under most physiological and pathogenic conditions, the mechanistic difference in physiologic versus pathogenic NF-B remains largely unknown. Recently, we have demonstrated, for the first time, that NF-B exhibits different activation patterns in normal and malignant lung epithelial cells, the first line of defense and a key component of the innate immunity in the lung. Furthermore, we have revealed, also for the first time, the PDZ-LIM domain-containing protein PDLIM2 as a tumor suppressor and ubiquitin E3 ligase that selectively degrades the ‘pathogenic’ form but not the ‘physiologic’ form of NF-B (thereby preventing pathogenic activation while allowing physiologic activation of NF-B by inflammatory stimuli) and can be targeted as mono- or combination therapy in authentic mouse models of human lung cancer. Like in human lung cancer, of note, PDLIM2 is repressed in the lungs of patients with chronic obstructive pulmonary disease (COPD) or interstitial lung diseases (ILDs), and PDLIM2 repression is associated with disease severity and poor patient survival. Lung epithelial-specific or global deletion of PDLIM2 renders mice highly susceptible to spontaneous and induced lung cancers as well as acute lung injury and death by the bacteria endotoxin lipopolysaccharide (LPS). Based on these trailblazing discoveries, in this proposal we will identify the functional partners of PDLIM2 and determine the biochemical mechanisms by which they act as a ubiquitin E3 ligase complex to dichotomize the differential activation of NF-B in lung epithelial cells. We will also determine in vivo and in vitro the roles and molecular mechanisms of this regulation in lung disease and host defense against pulmonary infection using conditional and inducible knockout (KO) or knock-in (KI) mice and cells of PDLIM2 and/or NF-B. These studies will improve our understanding of normal lung physiology and pulmonary diseases, and open new avenues to study NF-B regulation and action. They may also lead to new clinically feasible approaches to selectively target pathogenic NF-B and reveal new therapeutic targets for better lung disease treatment.