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

摘要 核因子-B在多种疾病的炎症和发病机制中起致病作用，如肺部疾病、 美国第三大杀手，造成七分之一的死亡。然而，我们一直无法 由于它在生理学中同样重要的作用，为了成功地将其用于临床治疗，尤其是， 先天免疫和宿主防御。梳理NF-B的这些功能将克服这一障碍 以一种强大的手段对抗肺部和其他疾病。尽管驱动NF-B激活的核心机制 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，机制 生理性和致病性的NF-B的差异仍然很大程度上是未知的。最近，我们展示了， 首次发现，NF-B在正常和恶性肺上皮细胞中表现出不同的激活模式， 肺的第一道防线，是先天免疫的重要组成部分。此外，我们已经透露， 也是第一次，含有PDZ-LIM结构域的蛋白PDLIM2作为肿瘤抑制因子和泛素E3 选择性地降解“致病”形式而不是“生理”形式的核因子-B的连接酶(从而防止 致病激活，同时允许通过炎症刺激对NF-B进行生理激活)，并且可以靶向 在人类肺癌的真实小鼠模型中进行单一或联合治疗。就像人类肺癌一样， 值得注意的是，PDLIM2在慢性阻塞性肺疾病(COPD)或 间质性肺疾病(ILDS)和PDLIM2抑制与疾病严重程度和贫困患者相关 生死存亡。肺上皮特异性或整体缺失PDLIM2使小鼠高度易感自发性 和诱发肺癌以及细菌内毒素内毒素引起的急性肺损伤和死亡 (LP)。基于这些开创性的发现，在本提案中，我们将确定PDLIM2的功能合作伙伴 并确定它们作为泛素E3连接酶复合体进行二分法的生化机制 肺上皮细胞中核因子-B的差异激活。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抗肺部感染中的分子机制 条件性和诱导性基因敲除(KO)或敲入(KI)小鼠以及PDLIM2和/或NF-B细胞。这些研究 将提高我们对正常肺生理和肺部疾病的了解，并开辟新的途径 研究核因子-B的调节和作用。它们还可能导致新的临床上可行的方法来选择性地靶向 致病核因子-B，为更好地治疗肺部疾病揭示新的治疗靶点。

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.