The role of alpha-T-catenin in the pathogenesis of occupational asthma

α-T-连环蛋白在职业性哮喘发病机制中的作用

• 批准号: 9325524
• 负责人: Stephen Sai Folmsbee
• 金额: $ 2.6万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9325524
• 关键词: Adult asthma; Age; Anti-Inflammatory Agents; Anti-inflammatory; Asthma; Binding; Biological; Blood Vessels; Cadherins; Cardiac; Cardiac Myocytes; Cardiomegaly; Cardiomyopathies; Cell Adhesion Molecules; Cell Culture Techniques; Cell Proliferation; Cell-Cell Adhesion; Cells; Clinical; Communication; Complex; Coupling; Cytoskeleton; Data; Defect; Desmosomes; Development; Disease; Dyes; Edema; Environmental Irritants; Epithelial; Etiology; Exposure to; Extrinsic asthma; Felis catus; Functional disorder; Future; Gap Junctions; Genotype; Growth; Heart; Hybrids; Immunologics; Incidence; Individual; Inflammation; Injectable; Intercellular Junctions; Knock-out; Knockout Mice; Link; Liquid substance; Lung; Measures; Mechanical ventilation; Mechanics; Mediating; Mediator of activation protein; Modeling; Mutation; Myocardium; Occupational Asthma; Occupations; Pathogenesis; Pathway interactions; Phenotype; Physiological; Physiology; Population; Pulmonary Edema; Pulmonary veins; Refractory; Respiratory physiology; Role; Severities; Single Nucleotide Polymorphism; Steroid Resistance; Testing; Testis; Tissues; Toluene Diisocyanate; Variant; Wild Type Mouse; Workplace; airway hyperresponsiveness; alphaT catenin; ataxia telangiectasia mutated protein; base; beta catenin; genome wide association study; improved; methacholine; mouse model; new therapeutic target; novel; plakophilin 2; prevent; public health relevance; relating to nervous system; targeted treatment

 DESCRIPTION (provided by applicant): 10-25% of adult asthma is occupation-induced, a subtype caused by exposure to environmental irritants in the workplace. Recently, a genome-wide association study (GWAS) identified single nucleotide polymorphisms (SNPs) in α-T-catenin (α-T-cat) that correlated with the incidence and severity of toluene diisocyanate (TDI) occupational asthma. α-T-cat is an essential mediator of cardiac cell-cell adhesion through linking the β-catenin/cadherin complex to the cytoskeleton, so a mechanism by which α-T-cat could contribute to TDI-asthma has been unclear. We find, however, that α-T-cat is indeed expressed in lung within the cardiomyocyte sheath of pulmonary veins (PV). How PV dysfunction might underlie asthma is not known, but α-T-cat knockout (KO) mice manifest enlarged hearts with disrupted junctions and reduced contractility, and we find that the cardiomyocyte sheath of PV may be similarly thickened, suggesting a lung phenotype/genotype correlate. We also find that using a TDI-based murine model of asthma, α-T-cat KO mice show increased airway hyperresponsiveness (AHR) to methacholine (mCh) when compared to WT mice, confirming that dysfunction of α-T-cat may increase the sensitivity for the development of TDI-asthma. Based on these preliminary data, we suspect α-T-cat dysfunction may contribute to asthma through a cardiac cell defect that leads to increased airway edema. α-T-cat loss causes heart enlargement, perhaps due to its effect on limiting tissue proliferation through the Hippo-Warts (HW) pathway, an established regulator of cardiac growth that can be inhibited by the highly related α-E-cat. In addition, cardiomyocytes of α-T-cat KO mice manifest a reduction in hybrid junctions, composed of cadherin, desmosome, and gap junction components, which are critical for coordinated contractility. Since α-T-cat can bind plakophilin-2 (PKP2), a component o desmosomes, we predict that a α-Tcat/PKP2 interaction is critical to both the assembly of hybrid junctions, gap junction communication and proliferation inhibition. Together, the proposed aims will allow us to test the hypothesis that α-T-cat dysfunction in cardiomyocytes disrupts gap junction communication and increases proliferation, which ultimately drive edematous changes that contribute to asthma. Together, these findings suggest that cardiac cell junction dysfunction may underlie occupational asthma. This is a novel mechanism and contributor to the pathogenesis of asthma, which has long been considered primarily a disease mediated by inflammation. By elucidating the influence of cardiac function on the development of asthma, we may be able to develop novel drugs targeting improving vascular and cardiac function to prevent or treat occupational asthma in susceptible individuals.

 描述（由申请人提供）：10-25%的成人哮喘是职业诱发的，是由工作场所暴露于环境刺激物引起的一种亚型。最近，一项全基因组关联研究（GWAS）发现α-T-catenin（α-T-cat）的单核苷酸多态性（SNPs）与甲苯二异氰酸酯（TDI）职业性哮喘的发病率和严重程度相关。α-T-cat通过β-catenin/cadherin复合物与细胞骨架连接，是心肌细胞间粘附的重要介质，因此α-T-cat参与TDI-哮喘的机制尚不清楚。然而，我们发现α-T-cat确实在肺静脉（PV）的心肌细胞鞘内表达。PV功能障碍如何成为哮喘的基础尚不清楚，但α-T-cat基因敲除（KO）小鼠表现出心脏增大，连接中断，收缩力降低，我们发现PV的心肌细胞鞘可能类似增厚，表明肺表型/基因型相关。我们还发现，使用基于TDI的哮喘小鼠模型，与WT小鼠相比，α-T-cat KO小鼠对乙酰甲胆碱（mCh）的气道高反应性（AHR）增加，证实α-T-cat功能障碍可能增加TDI哮喘发展的敏感性。基于这些初步数据，我们怀疑α-T-cat功能障碍可能通过心脏细胞缺陷导致气道水肿增加而导致哮喘。α-T-cat缺失导致心脏增大，这可能是由于其通过Hippo-Warts（HW）途径限制组织增殖的作用，HW途径是一种已确立的心脏生长调节因子，可被高度相关的α-E-cat抑制。此外，α-T-cat KO小鼠的心肌细胞表现出由钙粘蛋白、桥粒和间隙连接组分组成的杂交连接减少，这对协调收缩力至关重要。由于α-T-cat可以结合桥粒的一种组分--斑嗜蛋白2（PKP 2），因此我们预测α-Tcat/PKP 2相互作用对杂交连接的组装、间隙连接通讯和增殖抑制都是至关重要的。总之，提出的目标将使我们能够验证心肌细胞中α-T-cat功能障碍破坏间隙连接通讯并增加增殖的假设，这最终会导致导致哮喘的水肿变化。总之，这些发现表明心脏细胞连接功能障碍可能是职业性哮喘的基础。这是一种新的机制，也是哮喘发病机制的贡献者，长期以来，哮喘一直被认为主要是一种由炎症介导的疾病。通过阐明心脏功能对哮喘发生的影响，我们可能能够开发新的药物，以改善血管和心脏功能，以预防或治疗易感人群的职业性哮喘。