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Molecular Mechanisms Regulated by FOXM1 in Chronic Lung Remodeling

FOXM1在慢性肺重塑中调控的分子机制

基本信息

批准号：
10891764
负责人：
Vladimir Kalinichenko
金额：
$ 48.98万
依托单位：
UNIVERSITY OF ARIZONA
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：
2023-07-21 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10891764
关键词：
Molecular Mechanisms Regulated FOXM1 Chronic

项目摘要

PROJECT SUMMARY. COPD is a severe chronic respiratory disease, which is associated with smoking and characterized by chronic lung inflammation, emphysema, airway remodeling and goblet cell metaplasia. Identification of new molecular targets is needed to improve therapeutic outcomes in COPD patients. Our grant application will explore the role of Forkhead transcription factor FOXM1 as a potential therapeutic target in mouse and rat COPD models. FOXM1 is an embryonic transcription factor, which is not expressed in quiescent lungs but aberrantly induced during lung carcinogenesis. We provide preliminary data demonstrating that FOXM1 is activated in airway epithelial cells, macrophages and type II cells of COPD patients and mice exposed to cigarette smoke (CS). Increased expression of FOXM1 in mouse and human lungs is associated with emphysema and goblet cell metaplasia. Transgenic overexpression of FOXM1 in alveolar type II cells exacerbated lung inflammation, leading to emphysema. Genetic deletion of Foxm1 gene from myeloid cells, including macrophages and monocytes, decreased pulmonary inflammation after acute lung injury. Genetic ablation of Foxm1 from airway club cells decreased goblet cell metaplasia caused by house dust mite allergens. While FOXM1 is increased in human COPD and mouse genetic data suggest that FOXM1 is critical goblet cell metaplasia, pulmonary inflammation and alveolar remodeling, molecular mechanisms regulated by FOXM1 in COPD remain unknown. We propose to test the hypothesis that FOXM1 increases goblet cell metaplasia and emphysema in COPD by transcriptionally activating distinct sets of pro-inflammatory and mucinous genes in alveolar type II cells, airway club cells and macrophages. We will also test the therapeutic efficacy of novel FOXM1 inhibitor RCM-1 in mouse and rat COPD models. Chronic CS exposure and a combination of CS and Influenza infection will be used to induce pulmonary inflammation, emphysema and goblet cell metaplasia. In Aim 1, we will identify molecular mechanisms regulated by FOXM1 in alveolar type II cells (Aim 1A) and macrophages (Aim 1B) using purified cells and mice with specific ablation of Foxm1 gene from these cell types. FOXM1 targets will be validated using de-identified human COPD lungs. In Aim 2A, we will use mice with specific deletion of Foxm1 from airway club cells, to identify FOXM1 target genes critical for differentiation of club cells into goblet cells in COPD model. In Aim 2B, we will test therapeutic potential of novel, non-toxic FOXM1-inhibiting small molecule compound, RCM-1, which has been recently discovered in my lab using a high throughput screen. Altogether, these studies will identify novel molecular mechanisms critical for COPD pathogenesis and test therapeutic potential of FOXM1 inhibitors in animal COPD models.

项目总结。慢性阻塞性肺病是一种严重的慢性呼吸系统疾病，与吸烟和吸烟有关

项目成果

期刊论文数量（19）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Novel FOXF1-Stabilizing Compound TanFe Stimulates Lung Angiogenesis in Alveolar Capillary Dysplasia.

新型 FOXF1 稳定化合物 TanFe 刺激肺泡毛细血管发育不良的肺血管生成。

DOI：
10.1164/rccm.202207-1332oc
发表时间：
2023
期刊：
American journal of respiratory and critical care medicine
影响因子：
24.7
作者：
Pradhan,Arun;Che,Lixiao;Ustiyan,Vladimir;Reza,AbidA;Pek,NicoleM;Zhang,Yufang;Alber,AndreaB;Kalin,TimothyR;Wambach,JenniferA;Gu,Mingxia;Kotton,DarrellN;Siefert,MatthewE;Ziady,AssemG;Kalin,TanyaV;Kalinichenko,VladimirV
通讯作者：
Kalinichenko,VladimirV

Genome Editing for Rare Diseases.

DOI：
10.1007/s40778-020-00175-1
发表时间：
2020-09
期刊：
Current stem cell reports
影响因子：
1.4
作者：
Pradhan A;Kalin TV;Kalinichenko VV
通讯作者：
Kalinichenko VV

Generation of Pulmonary Endothelial Progenitor Cells for Cell-based Therapy Using Interspecies Mouse-Rat Chimeras.

使用种间小鼠-大鼠嵌合体生成肺内皮祖细胞用于基于细胞的治疗。

DOI：
10.1164/rccm.202003-0758oc
发表时间：
2021
期刊：
American journal of respiratory and critical care medicine
影响因子：
24.7
作者：
Wang,Guolun;Wen,Bingqiang;Ren,Xiaomeng;Li,Enhong;Zhang,Yufang;Guo,Minzhe;Xu,Yan;Whitsett,JeffreyA;Kalin,TanyaV;Kalinichenko,VladimirV
通讯作者：
Kalinichenko,VladimirV

Nanoparticle Delivery of STAT3 Alleviates Pulmonary Hypertension in a Mouse Model of Alveolar Capillary Dysplasia.

DOI：
10.1161/circulationaha.121.053980
发表时间：
2021-08-17
期刊：
Circulation
影响因子：
37.8
作者：
Sun F;Wang G;Pradhan A;Xu K;Gomez-Arroyo J;Zhang Y;Kalin GT;Deng Z;Vagnozzi RJ;He H;Dunn AW;Wang Y;York AJ;Hegde RS;Woods JC;Kalin TV;Molkentin JD;Kalinichenko VV
通讯作者：
Kalinichenko VV

Hypoxia represses FOXF1 in lung endothelial cells through HIF-1α.

DOI：
10.3389/fphys.2023.1309155
发表时间：
2023
期刊：
FRONTIERS IN PHYSIOLOGY
影响因子：
4
作者：
Acharya, Anusha;Bian, Fenghua;Gomez-Arroyo, Jose;Wagner, Kimberly A.;Kalinichenko, Vladimir V.;Kalin, Tanya V.
通讯作者：
Kalin, Tanya V.