The role of PUMA in the progression of cigarette smoking-induced COPD

PUMA 在吸烟引起的 COPD 进展中的作用

基本信息

批准号：
10930186
负责人：
Dongshi Chen
金额：
$ 41.4万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-22 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10930186
关键词：
Air Alveolar Animal Model Apoptosis Apoptosis Inhibitor Apoptotic Attenuated BCL2 gene Bronchoalveolar Lavage Cause of Death Cell Death Cell Death Induction Cell Death Inhibition Cells Chronic Obstructive Pulmonary Disease Chronic lung disease Cigarette smoke-induced emphysema Data Databases Development Disease Progression Elasticity Epithelial Cells Etiology Evaluation Exposure to Family member Foundations Genomics In Vitro Induction of Apoptosis Inflammation Inflammatory Inflammatory Response Inhibition of Apoptosis Investigation Knockout Mice Liquid substance Lung Lung diseases Macrophage Macrophage Activation Mediating Mitochondria Modeling Molecular Molecular Weight Mus Organoids Pathogenesis Patients Pattern Play Pre-Clinical Model Process Pulmonary Emphysema Pulmonary Inflammation Reporting Research Role Signal Pathway Smoking Structure of parenchyma of lung TNF gene TP53 gene Testing Therapeutic Uses Tissues airway obstruction cigarette smoke cigarette smoke-induced cigarette smoke-induced COPD cigarette smoking cytokine design effective therapy experimental study exposure to cigarette smoke improved in vivo inhibitor knock-down loss of function mortality neutrophil novel novel therapeutic intervention novel therapeutics pharmacologic pre-clinical prevent pulmonary function small molecule inhibitor smoking cessation targeted treatment therapeutic target

项目摘要

Abstract Chronic obstructive pulmonary disease (COPD) is the fourth-leading cause of mortality worldwide. The causes of COPD are usually determined by multiple factors, among which exposure to cigarette smoke (CS) is the most common cause of COPD. CS exposure has been reported to induce epithelial cell death by apoptosis and necroptosis, and trigger lung inflammation. Most previous studies on cell death focus on the mechanism of apoptosis. Necroptosis, a new form of cell death, has emerged as another important mechanism for COPD pathogenesis. Therefore, revealing a novel target for both apoptosis and necroptosis will help the development of new treatments for COPD. Our preliminary data show that p53 up-regulated modulator of apoptosis (PUMA), a pro-apoptotic BH3-only Bcl-2 family member, is markedly induced in the lung tissues of COPD patients and mice exposed to CS treatment, as well as in lung epithelial cells treated with air-liquid interface (ALI) CS exposure or cigarette smoking extract (CSE). PUMA deficiency protected against CSE-induced apoptosis and necroptosis in the lung epithelial cells, and mouse alveolar organoids. Depletion of PUMA in the lung epithelial cells also attenuated the macrophage inflammatory profile. Moreover, knockdown of PUMA has higher suppressive effect on pro-inflammatory cytokines induction by CSE exposure than inhibition of cell death, indicating that PUMA might have a new function in triggering inflammation besides cell death. PUMA knock-out mice showed decreased lung inflammation, apoptosis, and necroptosis after 2 months of CS exposure, and rescued lung function loss after 6 months of CS exposure. Based on these preliminary findings, we hypothesize that PUMA mediates CS-induced apoptosis and necroptosis, and contributes to lung inflammation in the pathogenesis of COPD. We further hypothesize that PUMA can be pharmacologically targeted as a novel therapy against COPD. Specifically, we will investigate the functional role of PUMA in CS-induced lung epithelial cell death, as well as inflammatory macrophage activation, and test whether PUMA deletion or inhibition by a first-in-class small molecule inhibitor can protect the lung from CS-induced emphysema. In the proposed studies, we will pursue these three specific aims: (1) Test the hypothesis that PUMA orchestrates CS-induced apoptosis and necroptosis. (2) Test the hypothesis that PUMA induction in lung epithelial cells triggers pro-inflammatory cytokines expression and causes cell death independent lung inflammation. (3) Test the hypothesis that inhibition of PUMA by small molecular weight inhibitors prevents the development of cigarette smoke-induced emphysema in mice. This project is expected to reveal a new function of PUMA in the pathogenesis of COPD, especially its novel function in the induction of inflammatory cytokines. The completion of the proposed studies will provide proof-of- principle evidence for targeting PUMA as a novel therapeutic approach for COPD treatment.

抽象的慢性阻塞性肺疾病（COPD）是全球第四大死因。原因 COPD的发生通常由多种因素决定，其中暴露于香烟烟雾（CS）是最重要的慢性阻塞性肺病的常见原因。据报道，CS暴露可通过细胞凋亡和诱导上皮细胞死亡坏死性凋亡，并引发肺部炎症。以往关于细胞死亡的研究大多集中在细胞死亡的机制上。细胞凋亡。坏死性凋亡是一种新的细胞死亡形式，已成为慢性阻塞性肺病的另一个重要机制发病。因此，揭示细胞凋亡和坏死性凋亡的新靶点将有助于开发 COPD 的新疗法。我们的初步数据表明 p53 上调细胞凋亡调节剂 (PUMA)，促凋亡 BH3 的 Bcl-2 家族成员，在 COPD 患者的肺组织中被显着诱导，并且接受 CS 治疗的小鼠以及接受气液界面 (ALI) CS 治疗的肺上皮细胞或香烟提取物（CSE）。 PUMA 缺乏可防止 CSE 诱导的细胞凋亡和坏死性凋亡在肺上皮细胞和小鼠肺泡类器官中。肺上皮细胞中 PUMA 的消耗也减弱巨噬细胞炎症特征。而且PUMA的击倒具有更高的抑制效果 CSE 暴露对促炎细胞因子的诱导作用大于对细胞死亡的抑制作用，表明 PUMA 除了细胞死亡之外，可能还具有引发炎症的新功能。 PUMA基因敲除小鼠显示 CS 暴露 2 个月后，肺部炎症、细胞凋亡和坏死性凋亡减少，并挽救了肺部接触 CS 6 个月后功能丧失。基于这些初步发现，我们假设 PUMA 介导 CS 诱导的细胞凋亡和坏死性凋亡，并有助于肺部炎症的发病机制慢性阻塞性肺病。我们进一步假设 PUMA 可以作为一种针对 COPD 的新疗法进行药理学靶向治疗。具体来说，我们将研究 PUMA 在 CS 诱导的肺上皮细胞死亡中的功能作用，以及炎症巨噬细胞激活，并测试 PUMA 是否缺失或被首创的小分子抑制分子抑制剂可以保护肺部免受CS引起的肺气肿的影响。在拟议的研究中，我们将追求这三个具体目标：(1) 检验 PUMA 协调 CS 诱导的细胞凋亡的假设坏死性凋亡。 (2) 检验肺上皮细胞中 PUMA 诱导触发促炎的假设细胞因子表达并导致细胞死亡独立的肺部炎症。 (3) 检验抑制的假设 PUMA 的小分子量抑制剂可预防香烟烟雾引起的肺气肿的发展在小鼠中。该项目有望揭示PUMA在COPD发病机制中的新功能，特别是其新颖的功能。具有诱导炎症细胞因子的功能。拟议研究的完成将提供证据- 将 PUMA 作为 COPD 治疗新方法的主要证据。