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Control of Fibrinolytic Pathways in Lung Disease

肺部疾病纤溶途径的控制

基本信息

批准号：
6827618
负责人：
Sreerama Shetty
金额：
$ 27.5万
依托单位：
UNIVERSITY OF TEXAS HLTH CTR AT TYLER
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-09-06 至 2005-08-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The urokinase (uPA)-urokinase receptor (uPAR) system is implicated in the pathogenesis of pulmonary inflammation and repair via proteolytic remodeling, regulation of cell migration and mitogenesis. Depressed uPA expression in the lungs of patients with ARDS or interstitial lung diseases potentiates fibrosing alveolitis. Work we published in the initial funding cycle of this grant shows that lung epithelial cells regulate both uPA and uPAR at the posttranscriptional level. We hypothesize that expression of uPA and uPAR by lung epithelial cells is regulated by novel posttranscriptional pathways and that these pathways influence epithelial cell responses in lung inflammation or repair. Our preliminary data support the hypothesis and show that phosphoglycerate kinase (PGK) and other newly recognized uPAR and uPA mRNA binding protein-mRNA interactions control uPAR and uPA expression by lung epithelial cells. These pathways are poorly understood at this time, representing an important gap in our understanding of the pathogenesis of lung injury and repair. Our Specific Aims are: 1) To determine how PGK and another newly recognized uPAR mRNA coding region binding protein regulate uPAR expression in lung epithelial cells. 2) To elucidate the role of newly recognized 3'-untranslated region (3'UTR) uPAR mRNA-binding protein interactions on uPAR expression. 3) To determine the mechanism(s) by which PGK and hnRNPC, another putative regulatory protein, regulate cytokine-mediated expression of uPAR in lung epithelial cells. 4) To characterize the uPA mRNABp and determine how it regulates uPA expression in lung epithelial cells. These studies build on work accomplished in the first funding cycle of this project to extend our understanding of mechanisms by which lung epithelial cells regulate uPAR and uPA expression and will hasten development of novel therapeutics for acute lung injury or pulmonary fibrosis.

描述（由申请人提供）：尿激酶（uPA）-尿激酶受体（uPAR）系统参与肺部炎症的发病机制，并通过蛋白水解重塑、细胞迁移调节和有丝分裂发生进行修复。在患有ARDS或间质性肺病的患者的肺中，uPA表达降低会增强纤维化肺泡炎。我们在该基金的初始资助周期中发表的工作表明，肺上皮细胞在转录后水平调节uPA和uPAR。我们推测肺上皮细胞uPA和uPAR的表达受新的转录后途径调节，这些途径影响肺炎症或修复中的上皮细胞反应。我们的初步数据支持这一假设，并表明磷酸甘油酸激酶（PGK）和其他新认识的uPAR和uPA mRNA结合蛋白-mRNA相互作用控制uPAR和uPA表达的肺上皮细胞。目前对这些途径的了解还很少，这代表了我们对肺损伤和修复发病机制的理解中的一个重要差距。我们的具体目标是：1）研究PGK和另一种新发现的uPAR mRNA编码区结合蛋白对肺上皮细胞uPAR表达的调节作用。2)阐明新发现的3 '非翻译区（3' UTR）uPAR mRNA结合蛋白相互作用对uPAR表达的作用。3)探讨PGK和hnRNPC（另一种推测的调节蛋白）对酪氨酸介导的肺上皮细胞uPAR表达的调控机制。4)为了表征uPA mRNABp并确定其如何调节肺上皮细胞中uPA的表达。这些研究建立在该项目第一个资助周期完成的工作基础上，以扩展我们对肺上皮细胞调节uPAR和uPA表达的机制的理解，并将加速急性肺损伤或肺纤维化的新型治疗方法的开发。

项目成果

期刊论文数量（16）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Urokinase induces activation of STAT3 in lung epithelial cells.

DOI：
10.1152/ajplung.00476.2005
发表时间：
2006-10
期刊：
American journal of physiology. Lung cellular and molecular physiology
影响因子：
0
作者：
S. Shetty;G. Rao;D. Cines;K. Bdeir
通讯作者：
S. Shetty;G. Rao;D. Cines;K. Bdeir

Urokinase receptor expression involves tyrosine phosphorylation of phosphoglycerate kinase.

尿激酶受体表达涉及磷酸甘油酸激酶的酪氨酸磷酸化。

DOI：
10.1007/s11010-009-0273-4
发表时间：
2010
期刊：
Molecular and cellular biochemistry
影响因子：
4.3
作者：
Shetty,Praveenkumar;Velusamy,Thirunavukkarasu;Bhandary,YashodharP;Liu,MingC;Shetty,Sreerama
通讯作者：
Shetty,Sreerama

Regulation of urokinase receptor expression by phosphoglycerate kinase.

磷酸甘油酸激酶对尿激酶受体表达的调节。