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Actin-myosin contractility promotes the development of chronic bronchitis

肌动蛋白-肌球蛋白收缩性促进慢性支气管炎的发展

基本信息

批准号：
10090618
负责人：
Venkataramana K Sidhaye
金额：
$ 41.91万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-02-01 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10090618
关键词：
Actins Adhesions Aerosols Affinity Apical Applications Grants Binding Cause of Death Cell Adhesion Cell Adhesion Molecules Cell Polarity Cell Shape Cell-Cell Adhesion Cells Chronic Chronic Bronchitis Chronic Obstructive Airway Disease Cytoskeletal Modeling Cytoskeleton Data Defect Development Drug toxicity E-Cadherin Epidermal Growth Factor Receptor Epithelial Epithelial Cells Event Exhibits Growth Factor Receptors Histologic Hospitalization Human In Vitro Intervention Ligands Light Link Lung MUC5AC gene Mammals Mechanics Membrane Modeling Molecular Mucins Mucous body substance Mus Myosin ATPase Myosin Type II Pathway interactions Patients Pharmaceutical Preparations Pharmacology Pharmacology Study Phenotype Phosphorylation Production Proteins Receptor Activation Regulation Research Personnel Risk Role Shapes Signal Transduction Therapeutic Time Tissues United States Work airway epithelium apical membrane basolateral membrane cigarette smoke cigarette smoke-induced clinically relevant exposure to cigarette smoke genetic manipulation in vivo knock-down monolayer mortality mouse model non-muscle myosin novel strategies paralogous gene patient subsets prevent receptor response

项目摘要

PROJECT SUMMARY Chronic Obstructive Pulmonary Disease (COPD) is the 3rd leading cause of death in the US with a large subset of patients exhibiting chronic bronchitis. At this time we have no medications to cure chronic bronchitis (CB). In the U.S., cigarette smoke (CS) is the primary insult, leading to CB; yet, we do not understand how CS alters the epithelium to promote the development of mucus. In our work, we found that chronic CS causes stiffening of the epithelial cell in order to impact on its shape and decrease cell-cell adhesion proteins such as E-cadherin, to prevent the formation of contacts between neighboring cells. In this proposal, we will decipher the effects of altered actin-myosin II contractility. We propose that this increase in cell contractility decreases the polarity of the epithelial cell to promote cell-signaling events, including the activation of the epithelial growth factor receptor (EGFR). EGFR activation, in turn, leads to changes associated with chronic bronchitis, such as the increase in Muc5AC production. We propose to study pharmacologic interventions to alter actin-myosin contractility to study its effects on E-cadherin, cell-cell adhesion, cell polarity with EGFR activation and Muc5AC production. In Aim 1, we will determine if CS causes myosin II-driven increases in actin-myosin contractility to decrease membrane E-cadherin and disrupting cell-cell adhesion. Specifically, we will dissect the molecular mechanisms by which CS increases actin-myosin contractility, and determine if manipulating this increase will alter E- cadherin levels and cell-cell adhesion. In Aim 2, we will determine if CS-induced increased actin-myosin II contractility causes the epithelial cell to increase aberrant EGFR activation. Specifically, we will determine if increased contractility alters the polarity of the epithelium to promote EGF receptor-ligand interaction on either the apical or basolateral membrane to increase EGFR activation. In Aim 3, we will determine if, in a mouse model, decreasing the actin-myosin contractility will reverse EGFR activation and Muc5AC production by the epithelium after chronic CS. We will determine if inhibiting actin-myosin II contractility in vivo prevents or abrogates the CS-induced increase in Muc5AC and mucin production evident in mice after chronic CS exposure. We have found that E-cadherin knockdown promotes EGFR activation in mice. Using our newly established model to knockdown E-cadherin in the mouse lung epithelium, we will assess if actin-myosin contractility is upstream of decreases in E-cadherin to cause EGFR activation and increased Muc5AC. This is a five year grant proposal from an Early Stage Investigator.

项目总结

项目成果

期刊论文数量（24）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Gestational Exposure to Sidestream (Secondhand) Cigarette Smoke Promotes Transgenerational Epigenetic Transmission of Exacerbated Allergic Asthma and Bronchopulmonary Dysplasia.

DOI：
10.4049/jimmunol.1700014
发表时间：
2017-05-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
0
作者：
Singh SP;Chand HS;Langley RJ;Mishra N;Barrett T;Rudolph K;Tellez C;Filipczak PT;Belinsky S;Saeed AI;Sheybani A;Exil V;Agarwal H;Sidhaye VK;Sussan T;Biswal S;Sopori M
通讯作者：
Sopori M

Why New Biology Must Be Uncovered to Advance Therapeutic Strategies for Chronic Obstructive Pulmonary Disease.

DOI：
10.1152/ajplung.00367.2020
发表时间：
2020-11
期刊：
American journal of physiology. Lung cellular and molecular physiology
影响因子：
0
作者：
Jennifer Nguyen;D. Robinson;V. Sidhaye
通讯作者：
Jennifer Nguyen;D. Robinson;V. Sidhaye

Epithelial plasticity in COPD results in cellular unjamming due to an increase in polymerized actin.

DOI：
10.1242/jcs.258513
发表时间：
2022-02-15
期刊：
Journal of cell science
影响因子：
4
作者：
Ghosh B;Nishida K;Chandrala L;Mahmud S;Thapa S;Swaby C;Chen S;Khosla AA;Katz J;Sidhaye VK
通讯作者：
Sidhaye VK

Loss of E-cadherin is causal to pathologic changes in chronic lung disease.