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VRAC and Rho in pulmonary EC proliferation

VRAC 和 Rho 在肺 EC 增殖中的作用

基本信息

批准号：
7371911
负责人：
David M RODMAN
金额：
$ 41.14万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-01 至 2008-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7371911
关键词：
1-Phosphatidylinositol 3-Kinase Abbreviations Acute Alkalinization Anions Attenuated Binding Proteins Blood Vessels CREB1 gene Calcium-Activated Potassium Channel Cations Cell Cycle Cell Proliferation Cells Chronic Complement Complement component C1s Cyclic AMP Data Development Disease Endothelial Cells Endothelium Gene Activation Gene Expression Growth Human Hypoxia Ion Channel Lead Lesion Link Lung MAP Kinase Gene MAPK14 gene Mediating Mitogen-Activated Protein Kinase Kinases Mitogen-Activated Protein Kinases Mitogens Monomeric GTP-Binding Proteins Numbers P2X-receptor Pathogenesis Pattern Peptide Signal Sequences Phosphoinositide-3-Kinase, Catalytic, Gamma Polypeptide Phosphotransferases Plasma Play Pulmonary Hypertension Pump Purinoceptor Receptor Activation Receptor Protein-Tyrosine Kinases Regulation Rho-associated kinase Role Signal Pathway Signal Transduction Stimulus Structure Swelling Testing Tyrosine Vascular Diseases Vascular Endothelial Growth Factors Welts Work angiogenesis base lung development lung hypoxia novel prevent programs receptor response rho shear stress size

项目摘要

DESCRIPTION (provided by applicant): Proliferation of pulmonary endothelial cells (EC) is required for normal lung development and is involved in the pathogenesis of the vaso-occlusive plexiform lesions that complicate advanced pulmonary hypertension. The role of ion channels in regulating pulmonary EC cell cycle has not been fully elucidated. Recently, volume-regulated anion channels (VRAC) have been implicated in modulating angiogenesis. These channels are classically associated with the current activated by cell swelling (Icswell). We provide evidence that the EC mitogen VEGF activates VRAC, swelling and VEGF activate distinct signaling pathways, and blockade of VRAC completely inhibits proliferation of human pulmonary microvascular EC (HPMVEC). Based on this information we hypothesize: Activation of VRAC is a critical step in mitogenic stimulation of pulmonary endothelial cells, Divergent signaling pathways activated by endothelial cell swelling or mitogens result in tmique patterns of gene activation and Acute and chronic hypoxia activate VRAC and gene expression utilizing similar signaling pathways to cell swelling and mitogens, respectively. We propose three specific aims: 1) Test the hypothesis in human PMVEC that while mitogens and cell swelling both activate VRAC, distinct upstream signaling pathways link the stimuli to channel activation. 2) Test the hypothesis that mitogens and cell swelling activate unique patterns of gene expression dependent both on activation of VRAC and the distinct signaling pathways associated with VRAC activation. 3) Test the hypothesis that acute and chronic hypoxia act via mechanisms similar to cell swelling and mitogens, respectively. Upon completion of our studies we anticipate having more fully defined the role of VRAC and associated signaling pathways in regulation of pulmonary endothelial cell proliferation; work we anticipate will provide important clues to the pathogenesis of pulmonary vascular disease.

描述（由申请人提供）：