PKC Signaling in Thrombin-Activated Lung Fibroblasts

凝血酶激活的肺成纤维细胞中的 PKC 信号转导

基本信息

批准号：
6622381
负责人：
GALINA S BOGATKEVICH
金额：
$ 5.63万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-01-01 至
项目状态：
未结题

项目摘要

DESCRIPTION (provided by applicant):Scleroderma (systemic sclerosis, SSc) is an autoimmune, connective tissue disease characterized by microvascular injury and fibrosis, affecting 250,000 people (mostly women) in the USA. A leading cause of death in scleroderma patients is pulmonary dysfunction as a result of progressive interstitial lung fibrosis. It is postulated that activated fibroblasts (myofibroblasts) are involved in the pathogenesis of lung fibrosis. One mediator of lung fibroblast activation is thrombin, a multifunctional serine protease and G-protein coupled receptor ligand, which is generated immediately at sites of vascular injury. Recently we observed that exposure of normal cultured human lung fibroblasts to thrombin induces the myofibroblast phenotype. This change to an SSc phenotype occurs via protein kinase C epsilon (PKC-e) signal transduction. These observations open an interesting avenue in the investigation of the pathogenesis of SSc. Our overlying hypothesis is that thrombin triggers distinct PKC signaling mechanisms in normal and SSc lung fibroblasts. Specificity of the responses mediated in these two cell types can be explained by interaction of PKC with specific anchoring proteins. Better understanding of the mechanisms of these interactions may provide a useful target for novel therapeutic interventions in scleroderma lung disease, for which no proven, effective therapy exists.

描述（由申请人提供）：硬皮病（系统性硬化症，SSc）是一种以微血管损伤为特征的自身免疫性结缔组织疾病和纤维化，影响了美国 250,000 人（主要是女性）。一个主要原因硬皮病患者的死亡原因是肺功能障碍进行性肺间质纤维化。假设已激活成纤维细胞（肌成纤维细胞）参与肺纤维化的发病机制。肺成纤维细胞活化的一种介质是凝血酶，它是一种多功能的丝氨酸蛋白酶和 G 蛋白偶联受体配体，产生立即针对血管损伤部位。近期我们观察到曝光正常培养的人肺成纤维细胞凝血酶诱导肌成纤维细胞表型。 SSc 表型的这种变化是通过蛋白激酶 C epsilon 发生的 (PKC-e)信号转导。这些观察开辟了一条有趣的途径 SSc 发病机制的研究。我们的首要假设是凝血酶在正常和 SSc 肺中触发不同的 PKC 信号传导机制成纤维细胞。这两种细胞类型介导的反应的特异性可以可以通过 PKC 与特定锚定蛋白的相互作用来解释。更好的了解这些相互作用的机制可能会提供有用的信息硬皮病肺部疾病的新治疗干预目标目前还没有经过证实的有效疗法。