REGULATION OF MUCOUS CELL METAPLASIA IN ASTHMA

哮喘粘液细胞化生的调节

• 批准号: 7842533
• 负责人: Yohannes Tesfaigzi
• 金额: $ 64.2万
• 依托单位: LOVELACE BIOMEDICAL & ENVIRONMENTAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7842533
• 关键词: Abbreviations; Address; Alcian Blue; Allergens; Apoptosis; Apoptotic; Appearance; Asthma; BI-1; Basal lamina; Bronchioles; Cell Death; Cell Line; Cell Nucleus; Cells; Cessation of life; Chronic; Complex; Development; Endoplasmic Reticulum; Epidemiologic Studies; Epithelial Cells; Epithelium; Event; Exposure to; Family member; Figs - dietary; Funding; Glutathione S-Transferase; Goals; HSPB1 gene; Human; Hyperplasia; Infection; Inflammatory Response; Interferons; Lead; Malignant neoplasm of lung; Mediating; Messenger RNA; Metaplasia; Molecular; Mucins; Mucous body substance; Mus; Noxae; Nuclear Translocation; Ovalbumin; Pathway interactions; Patients; Peptides; Periodic acid Schiff stain method; Phenotype; Phosphorylation; Process; Proliferating; Proteins; Regulation; Resistance; Resolution; Rest; Risk; Role; STAT1 gene; Signal Transduction; Site; Testing; airway remodeling; base; cell type; crosslink; endoplasmic reticulum stress; high risk; in vivo; inhibitor/antagonist; killings; mRNA Expression; neoplastic cell; overexpression; public health relevance; therapy development

DESCRIPTION (provided by applicant): In patients with asthma mucous cells appear in airways that are normally devoid of these cells. This phenotype is called mucous cell metaplasia (MCM). MCM poses a serious risk because acutely secreted mucus can reduce airflow or can sometimes completely obstruct the airways and lead to death of asthmatics. In addition, epidemiological studies suggest that patients with chronic MCM are at a higher risk of developing lung cancer. Our studies demonstrated that IFN? and STAT1 signaling are crucial for the resolution of MCM by inducing cell death in airway epithelial cells (AECs). Therefore, this renewal application is focused on delineating the molecular mechanisms by which IFN? induces cell death in AECs. IFN? activates ERK1/2 and translocates Bax to the endoplasmic reticulum (ER) and reduces MCM. We found that Bik, a Bcl-2 family member that localizes to the ER, was significantly reduced in AECs obtained by bronchial brushings from asthmatics compared to controls. AECs from bik-/- mice were unaffected by IFN?, and Bik overexpression caused activation of ERK1/2 and induced killing in AECs. Noxa, another Bcl-2 family member, is induced by IFN? and enhances Bik-induced apoptosis. Noxa interacts with phosphorylated HSP27, reduces I?B levels, co-localizes with NF-?B, and reduces Bcl-2 mRNA expression. These findings led us to the following hypothesis: IFN?-induced cell death is mediated by Bik-induced activation of ERK1/2 that results in the translocation of Bax to the ER to initiate apoptosis. Furthermore, the Bik-mediated apoptosis is enhanced by Noxa through its interaction with phopho-HSP27 to degrade I?B1 but inhibit nuclear translocation of activated NF-?B and decrease Bcl-2 expression. We will test this hypothesis by: (1) Investigating whether Bik is central for the IFN?-induced cell death and resolution of MCM by activating ERK1/2 and translocating Bax to the ER. (2) Determining whether Noxa cross-linked to phosphorylated HSP27 facilitates NF-?B activation but inhibits nuclear translocation of NF-?B and thereby decreases Bcl-2 mRNA expression to enhance Bik-induced cell death and to identify the domain of Noxa-HSP27 interaction. (3) Determining whether Bik-induced ER stress requires Bax and Bak for the resolution of MCM during prolonged exposure to allergen. Understanding the role of these proteins in the resolution process of MCM may allow us to reduce hyperplastic epithelial cells that can secrete excessive mucus in asthmatics without compromising the resting epithelial cells and therefore the barrier functions of the epithelium. Development of targeted approaches to reduce MCM may also be useful for eliminating pre-neoplastic cells in patients with an increased risk of developing lung cancer. PUBLIC HEALTH RELEVANCE. Increased number of mucous cells in the airways poses a serious risk because acutely secreted mucus can reduce airflow or can sometimes completely obstruct the airways and lead to death of asthmatics. The proposed studies will dissect the molecular sequence of events that underlies the normal resolution process for these mucous cells during prolonged exposure to allergen in normal mice. Understanding these molecular processes may provide new strategies for reducing mucous secretions by eliminating hyperplastic mucous cells.

描述（由申请人提供）：在哮喘粘液细胞患者中，出现在通常没有这些细胞的气道中。该表型称为粘液细胞化生（MCM）。 MCM构成了严重的风险，因为急性分泌的粘液可以减少气流，或者有时会完全阻碍气道并导致哮喘患者死亡。此外，流行病学研究表明，患有慢性MCM的患者患肺癌的风险更高。我们的研究表明IFN？ STAT1信号传导对于通过诱导气道上皮细胞（AEC）中的细胞死亡（AEC）诱导细胞死亡的分辨率至关重要。因此，这种更新应用的重点是描述IFN的分子机制？在AEC中诱导细胞死亡。 ifn？激活ERK1/2并将Bax迁移到内质网（ER）并减少MCM。我们发现，与对照组相比，通过来自哮喘患者的支气管刷子获得的AEC，BCL-2家族成员BIK显着降低了AEC。来自BIK - / - 小鼠的AEC不受IFN的影响，而Bik过表达引起ERK1/2的激活并在AEC中诱导杀死。 NOXA是另一个BCL-2家庭成员，是由IFN诱导的？并增强BIK诱导的凋亡。 NOXA与磷酸化的HSP27相互作用，降低I？B水平，与NF-？B共定位，并降低Bcl-2 mRNA表达。这些发现使我们提出了以下假设：IFN？诱导的细胞死亡是由BIK诱导的ERK1/2激活介导的，从而导致Bax转移到ER以启动凋亡。此外，NOXA通过与Phopho-HSP27的相互作用来增强BIK介导的凋亡，从而降解I？B1，但抑制了活化的NF-？B的核易位并降低Bcl-2的表达。我们将通过：（1）研究BIK是否通过激活ERK1/2并将BAX转移到ER的IFN诱导的MCM的细胞死亡和分辨率。 （2）确定NOXA与磷酸化的HSP27交联是否有助于NF-？B激活，但抑制NF-？B的核易位，从而降低Bcl-2 mRNA的表达，从而增强BIK诱导的细胞死亡并确定NOXA-HSP27相互作用的结构域。 （3）确定BIK诱导的ER应力是否需要BAX和BAK在长时间暴露于过敏原的过程中分辨MCM的分辨率。了解这些蛋白质在MCM分辨率过程中的作用可能使我们能够减少增生的上皮细胞，这些细胞可以在不损害静息上皮细胞的情况下分泌哮喘中过量的粘液，从而损害上皮细胞的障碍功能。靶向方法减少MCM的开发也可能有助于消除患有肺癌风险增加的患者的肿瘤前细胞。公共卫生相关性。气道中的粘液细胞数量增加会带来严重的风险，因为急性分泌的粘液可以减少气流，或者有时会完全阻碍气道并导致哮喘患者死亡。拟议的研究将剖析事件的分子序列，这些事件是在正常小鼠中长时间暴露于过敏原的长期暴露期间这些粘液细胞正常分辨率过程的基础。了解这些分子过程可能会通过消除增生性粘液细胞来减少粘液分泌的新策略。