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Role of FBXO24 mediated ubiquitination of FoxP1 protein in the pathogenesis and treatment of COPD

FBXO24介导的FoxP1蛋白泛素化在COPD发病机制和治疗中的作用

基本信息

批准号：
10634617
负责人：
Divay Chandra
金额：
$ 46万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-15 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10634617
关键词：
ATF6 gene Adenoviruses Air Apoptosis Apoptosis Promoter Award Binding Binding Sites Biological Assay Cause of Death Cell Line Cells ChIP-seq Chronic Obstructive Pulmonary Disease Cigarette smoke-induced emphysema DNA Sequence Data Development Disease EIF-2alpha Epithelial Cells Epithelium GRP78 gene Genes Genome HepG2 Human Immunofluorescence Immunologic In Situ Nick-End Labeling In Vitro Induction of Apoptosis Intranasal Administration Knowledge Length Link LoxP-flanked allele Luciferases Lung Maps Mediating Mediator Messenger RNA Mus Mutagenesis PAWR protein Pathogenesis Phosphorylation Pre-Clinical Model Probability Promoter Regions Proteins Pulmonary Emphysema Quality Control Reporter Repression Role Stains Testing Therapeutic Transcription Repressor Ubiquitination Work airway epithelium airway obstruction biobank cigarette smoke cigarette smoke-induced cohort computer studies efficacy testing exposure to cigarette smoke forkhead protein human embryonic stem cell in vivo multicatalytic endopeptidase complex mutant novel overexpression preservation prevent promoter response transcription factor CHOP treatment strategy ubiquitin-protein ligase

项目摘要

PROJECT SUMMARY/ABSTRACT COPD is the fourth leading cause of death in the US; however, we do not fully understand the pathogenesis of COPD and lack disease-modifying therapies. Forkhead box protein P1 (FoxP1) is a transcriptional repressor that participates in lung epithelial development. Recent data from the UK Biobank, ECLIPSE, and COPDGene cohorts implicate FoxP1 as an important predictor of airflow limitation. However, a role for FoxP1 in the pathogenesis of COPD remains unexamined. Preliminary work suggests that FoxP1 protein is reduced while FoxP1 mRNA is increased in the lungs of humans and mice with COPD compared with controls. Specifically, we find that exposure to cigarette smoke causes the E3 ligase FBXO24 to ubiquitinate FoxP1, resulting in its proteasomal degradation in lung epithelial cells in vitro. The resulting loss of FoxP1 protein increases FoxP1 mRNA because FoxP1 is known to repress its own promoter. Unexpectedly, loss of FoxP1 protein increases activity of the unfolded protein response (UPR) as well as levels of the UPR’s apoptosis inducer C/EBP-homologous protein (CHOP) in lung epithelial cells. Analyses of publicly available FoxP1 ChIP-seq data demonstrates significant enrichment for FoxP1 binding sites in the promoters of key UPR genes and CHOP in human embryonic stem cells and HepG2 cells. Further, computational studies identify high probability binding sites for FoxP1 in the DNA sequence of UPR and CHOP promoters. In vivo, deletion of CHOP reduces apoptosis and emphysema in the lung. Finally, inducible deletion of FoxP1 by intranasal administration of Cre expressing adenovirus to floxed FoxP1 mice increased cigarette smoke induced emphysema. Therefore, we hypothesize that cigarette smoke causes FBXO24 to ubiquitinate and degrade FoxP1 protein in the lung epithelium thereby increasing promotor activity for key UPR genes and CHOP and inducing apoptosis and emphysema. During this award, we will: (1) Test the hypothesis that FoxP1 binds to and suppresses the promoters of key UPR genes and CHOP in lung epithelial cells by CUT&RUN and luciferase reporter assays, as well as map FoxP1 binding sites via promoter mutagenesis studies; (2) Test the hypothesis that deleting the FoxP1 gene in the lung epithelium will increase cigarette smoke induced UPR activity, CHOP, and apoptosis in the lung epithelium, and increase emphysema; and (3) Test the hypothesis that deleting the FBXO24 gene will prevent cigarette smoke induced degradation of FoxP1 protein and reduce cigarette smoke induced UPR activity, CHOP and apoptosis in the lung epithelium, and decrease emphysema. This proposal will investigate the mechanism for a novel link between FoxP1 and the UPR, demonstrate the functional impact of this mechanism in vivo, and test the efficacy of counteracting FBXO24 as a therapeutic strategy for COPD in preclinical models. This proposal reflects our long-term objective of developing new mechanism-based therapies that may have unprecedented disease modifying ability in COPD.

项目总结/文摘

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The FoxP1 gene regulates lung function, production of matrix metalloproteinases and inflammatory mediators, and viability of lung epithelia.

DOI：
10.1186/s12931-022-02213-4
发表时间：
2022-10-11
期刊：
Respiratory research
影响因子：
5.8
作者：
通讯作者：

Deep-Masker: A Deep Learning-based Tool to Assess Chord Length from Murine Lung Images.

Deep-Masker：一种基于深度学习的工具，用于评估小鼠肺部图像的弦长。

DOI：
10.1165/rcmb.2023-0051ma
发表时间：
2023
期刊：
American journal of respiratory cell and molecular biology
影响因子：
6.4
作者：
Pu,Jiantao;Leme,AdrianaS;deLimaESilva,Camilla;Beeche,Cameron;Nyunoya,Toru;Königshoff,Melanie;Chandra,Divay
通讯作者：
Chandra,Divay

Stain-Free total-protein normalization enhances the reproducibility of Western blot data.

DOI：
10.1016/j.ab.2022.114840
发表时间：
2022-10-01
期刊：
Analytical biochemistry
影响因子：
2.9
作者：
通讯作者：

Pulmonary comorbidities in psoriasis are associated with a high risk of respiratory failure.

DOI：
10.1177/03000605231182881
发表时间：
2023-06
期刊：
The Journal of international medical research
影响因子：
0
作者：
通讯作者：

Cross-Regulation of F-Box Protein FBXL2 with T-bet and TNF-α during Acute and Chronic Lung Allograft Rejection.

DOI：
10.4049/jimmunol.2200245
发表时间：
2022-11-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
0
作者：
Das A;Wang X;Wei J;Hoji A;Coon TA;Popescu I;Brown M;Frizzell S;Iasella CJ;Noda K;Sembrat JC;Devonshire K;Hannan SJ;Snyder ME;Pilewski JM;Sanchez PG;Chandra D;Mallampalli RK;Alder JK;Chen BB;McDyer JF
通讯作者：
McDyer JF