Genistein and Asthma Pathogenesis

金雀异黄素和哮喘发病机制

基本信息

批准号：
7110562
负责人：
RAVI KALHAN
金额：
$ 6.38万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-07-01 至 2007-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7110562
关键词：
JUN kinase asthma cell differentiation cell transformation chemoprevention cytoprotection fibroblasts fibrosis focal adhesion kinase gene induction /repression genetic transcription genistein kinase inhibitor postdoctoral investigator protein tyrosine kinase transforming growth factors

项目摘要

DESCRIPTION (provided by applicant): Airway remodeling in asthma results in irreversible airflow obstruction. Genistein is a dietary isoflavone and tyrosine kinase inhibitor found in soy. An epidemiologic study revealed that subjects with asthma having higher genistein intake have less airflow obstruction. In animal asthma models, genistein reduces bronchoconstriction, lung leukotriene levels, and airway eosinophilia. We found that genistein impairs eosinophil leukotriene synthesis and inhibits the transformation of fibroblasts to myofibroblasts, a key phenotypic change of the remodeled airway. We hypothesize that genistein blocks the transformation of lung fibroblasts to myofibroblasts by inhibiting TGF-beta1- and integrin-induced intracellular signaling. We test genistein's ability to inhibit TGF-beta1 stimulated activation of Smad-transcription factors, p38, and JNK. We evaluate genistein's effects on TGF-beta1- and integrin-stimulated activation of focal adhesion kinase (FAK) and src, and the downstream consequences of blocking FAK and src on JNK and p38. Exploring these mechanisms will expand the scientific rationale for tyrosine kinase inhibition as a therapeutic approach to asthmatic airway remodeling, and justify further study of the therapeutic role of soy isoflavones.

描述（由申请人提供）：哮喘的气道重塑导致不可逆的气流阻塞。染料木黄酮是在大豆中发现的一种饮食中异黄酮和酪氨酸激酶抑制剂。一项流行病学研究表明，哮喘摄入量较高的受试者的气流阻塞较少。在动物哮喘模型中，染料木黄酮降低了支气管收缩，肺白细胞水平和气道嗜酸性粒细胞。我们发现染料木黄酮会损害白细胞嗜酸性粒细胞的合成，并抑制成纤维细胞转化为肌纤维细胞，这是重塑气道的关键表型变化。我们假设染料木黄酮通过抑制TGF-BETA1-和整联蛋白诱导的细胞内信号传导来阻止肺成纤维细胞向肌纤维细胞的转化。我们测试了染料木黄酮抑制TGF-BETA1刺激Smad转录因子P38和JNK激活的能力。我们评估了染料蛋白酶对焦点粘附激酶（FAK）和SRC的TGF-BETA1和整合素刺激的激活的影响，以及阻断FAK和SRC对JNK和p38的下游后果。探索这些机制将扩大酪氨酸激酶抑制作用的科学原理，作为一种治疗性气道重塑的治疗方法，并证明进一步研究大豆异黄酮的治疗作用。