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-B在各种疾病（例如肺脱毛虫的酶）中发挥了致病作用IND发病机理， 美国的第三个领先杀手造成了七分之一的死亡。 由于它在生理学中的重要角色，尤其是 免疫和宿主防御。 用强大的手段与其他疾病作斗争。 在大多数生理学条件下，已经定义得很好，并且是相同的机械条件 我们已经证明，生理学与致病性NF-B的差异仍然很大。 NF-B首次表现出正常和恶性肺脊髓细胞中的差异模式， 第一道防线和肺部先天性的关键组成部分。 同样，含PDZ-LIM域PDLIM2 PDLIM2高达和泛素E3 有选择地降解“致病性”形式但nf-b的“生理学”形式的连接酶（从而 致病激活，同时允许通过炎症刺激对NF-B进行生理激活），并且可以针对性 作为人类肺罐头正宗鼠的单或联合疗法。 值得注意的是，PDLIM2在慢性阻塞性肺（COPD）或或 间质性肺部疾病（ILDS）和PDLIM2抑制。 生存。 和诱发的肺癌以及急性肺损伤和死亡的肺内毒素脂多糖死亡 （lps）。 并确定它们充当泛素E3连接酶复合物的生化机制 肺上皮细胞中NF-的差异激活。 该调节中这种调节的分子机制在肺部疾病和使用使用 有条件的和诱导的敲除（KO）或敲除（Ki）小鼠和PDLIM2和/或NF-B的细胞 将提高我们对正常肺部生理学和肺部疾病的理解，并开放新的途径 研究NF-B调节和行动。 致病性NF-B并揭示了用于更好肺部疾病治疗的新疗法靶标。