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

行政补充：泛素 E3 连接酶 PDLIM2 在肺先天免疫和疾病中对 NF-kappaB 调节的剖析

• 批准号: 10784300
• 负责人: Zhaoxia Qu
• 金额: $ 21.08万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-10 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10784300
• 关键词: Acetylation; Acute Lung Injury; Administrative Supplement; Age; Automobile Driving; Bacteria; Binding; Biochemical; Biological Assay; Cell Line; Cells; Cessation of life; Chronic Obstructive Pulmonary Disease; Clinical; Clinical Treatment; Combined Modality Therapy; Complex; Data; Deacetylation; Disease; Dissection; Endotoxins; Epithelial Cells; Epithelium; Exhibits; Functional disorder; Genetic Transcription; Host Defense; Human; Immunology procedure; In Vitro; Incidence; Infection; Inflammation; Inflammatory; Interstitial Lung Diseases; Investigation; Knock-in Mouse; Knock-out; Knockout Mice; LIM Domain; Lipopolysaccharides; Lung; Lung Neoplasms; Lung diseases; Lung infections; Malignant - descriptor; Malignant neoplasm of lung; Mediating; Modification; Molecular; Morbidity - disease rate; Mus; NF-kappa B; Natural Immunity; Nuclear; Outcome; Pathogenesis; Pathogenicity; Pathologic; Patients; Pattern; Physiological; Physiology; Play; Predisposition; Proteins; RELA gene; Regulation; Repression; Ring Finger Domain; Role; Safety; Severities; Severity of illness; Signal Transduction; Stimulus; Testing; Time; Tumor Suppressor Proteins; Ubiquitination; United States; Woman; chromatin immunoprecipitation; conditional knockout; fighting; human model; improved; in vivo; innovation; lung injury; lung tumorigenesis; member; men; mimetics; mortality; mouse model; neoplastic cell; new therapeutic target; novel; novel therapeutics; prevent; recruit; single-cell RNA sequencing; ubiquitin-protein ligase

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.

抽象的 NF-κB 在炎症和多种疾病的发病机制中发挥着致病作用，例如肺部疾病、 美国第三大杀手，造成七分之一的死亡。然而，我们却无能为力。 由于其在生理学中同样重要的作用，因此能够成功地将其用于临床治疗，特别是， 区分 NF-κB 的先天免疫和宿主防御功能将克服这一障碍。 虽然驱动 NF-κB 激活的核心机制是对抗肺部和其他疾病的有力手段。 已被明确定义，并且在大多数生理和致病条件下都是相同的，其机制 最近，我们已经证明，生理性 NF-κB 与致病性 NF-κB 之间的差异仍然很大程度上未知。 首次发现 NF-κB 在正常和恶性肺上皮细胞中表现出不同的激活模式， 肺部的第一道防线和先天免疫的关键组成部分此外，我们还发现， 也是首次，含有PDZ-LIM结构域的蛋白PDLIM2作为肿瘤抑制因子和泛素E3 连接酶选择性地降解“致病”形式，但不降解“生理”形式的 NF-κB（从而防止 病原体激活，同时允许炎症刺激对 NF-κB 进行生理激活）并且可以靶向 作为人类肺癌真实小鼠模型的单一或联合治疗，就像人类肺癌一样， 值得注意的是，PDLIM2 在慢性阻塞性肺病 (COPD) 患者的肺部受到抑制，或者 间质性肺疾病 (ILD) 和 PDLIM2 抑制与疾病严重程度和贫困患者相关 肺上皮特异性或整体缺失 PDLIM2 使小鼠高度易感自发性生存。 细菌内毒素脂多糖诱发肺癌以及急性肺损伤和死亡 (LPS)。基于这些开创性的发现，在本提案中，我们将确定 PDLIM2 的功能伙伴。 并确定它们作为泛素 E3 连接酶复合物以二分法的生化机制 我们还将确定 NF-κB 在肺上皮细胞中的差异激活在体内和体外的作用。 以及肺部疾病和宿主防御肺部感染的这种调节的分子机制 这些研究涉及 PDLIM2 和/或 NF-κB 的条件性和诱导性敲除 (KO) 或敲入 (KI) 小鼠和细胞。 将提高我们对正常肺部生理学和肺部疾病的了解，并开辟新的途径 研究 NF-κB 的调节和作用也可能导致新的临床可行的选择性靶向方法。 致病性 NF-κB 并揭示更好的肺部疾病治疗的新治疗靶点。