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.

项目摘要慢性阻塞性肺疾病（COPD）是美国的第三大死亡原因表现出慢性支气管炎的患者。目前，我们没有治愈慢性支气管炎（CB）的药物。在美国，香烟烟（CS）是主要的侮辱，导致CB；但是，我们不明白CS如何改变上皮促进粘液的发展。在我们的工作中，我们发现慢性CS导致僵硬上皮细胞以影响其形状并降低细胞 - 细胞粘附蛋白，例如电子钙粘着蛋白防止相邻细胞之间的接触形成。在此提案中，我们将破译肌动蛋白肌球蛋白II的收缩性改变了。我们建议细胞收缩力的增加会降低促进细胞信号事件的上皮细胞，包括上皮生长因子受体的激活（egfr）。 EGFR激活又导致与慢性支气管炎有关的变化，例如增加 MUC5AC生产。我们建议研究药理干预措施，以将肌动蛋白肌球蛋白收缩性改变为研究其对E-钙粘蛋白，细胞 - 细胞粘附，EGFR激活和MUC5AC产生的影响。在 AIM 1，我们将确定CS是否导致肌动蛋白II驱动的肌动蛋白肌球蛋白收缩力增加膜电子钙粘蛋白和破坏细胞细胞粘附。具体而言，我们将剖析分子机制 CS增加肌动蛋白肌球蛋白的收缩力，并确定操纵这种增加是否会改变E- 钙粘蛋白水平和细胞粘附。在AIM 2中，我们将确定CS诱导的肌动蛋白肌球蛋白II是否增加收缩力导致上皮细胞增加异常的EGFR激活。具体来说，我们将确定是否提高收缩性会改变上皮的极性，以促进任何任一的EGF受体 - 配体相互作用顶端或基底外侧膜增加EGFR激活。在AIM 3中，我们将确定是否在鼠标中模型，降低肌动蛋白肌球蛋白的收缩力将逆转EGFR激活和MUC5AC的产生慢性CS后上皮。我们将确定在体内抑制肌动蛋白肌动蛋白II的收缩力是否可以防止或废除了慢性CS后CS诱导的MUC5AC和粘蛋白产生的增加的增加接触。我们发现E-钙粘蛋白敲低促进小鼠的EGFR激活。使用我们的新在小鼠肺上皮中敲低E-钙黏着蛋白的既定模型，我们将评估肌动蛋白肌球蛋白是否收缩性是E-钙粘着蛋白下降的上游，导致EGFR激活和MUC5AC增加。这是一个早期调查员的五年赠款提案。

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.