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The Role of CLIC4 in Angiogenesis

CLIC4 在血管生成中的作用

基本信息

批准号：
8470213
负责人：
JOHN C EDWARDS
金额：
$ 35.88万
依托单位：
SAINT LOUIS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-17 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8470213
关键词：
Acids Address Affect Back Biochemical Biological Assay Blood Vessels Blood capillaries CLIC4 gene Caenorhabditis elegans Capillary Endothelial Cell Cell Proliferation Cell fusion Cell membrane Cells Cessation of life Chloride Channels Chloride Ion Chlorides Coronary Arteriosclerosis Coupled Data Defect Deletion Mutation Development Diabetes Mellitus Disease Electrophoresis Embryo Endothelial Cells Environment Failure Family Family member Goals Growth Health Heart Diseases In Vitro Individual Intracellular Membranes Ion Channel Ions Lead Malignant Neoplasms Maps Mass Spectrum Analysis Measures Mediator of activation protein Membrane Membrane Fusion Membrane Protein Traffic Migraine Modification Molecular Morphogenesis Mus Nephrotic Syndrome Pathway interactions Permeability Physiological Pilot Projects Pinocytosis Plasma Play Point Mutation Prevention Process Property Protein Family Proteins Proton Pump Reagent Recombinants Regulation Risk Role Science Signal Transduction Staging Stimulus Stroke Structure-Activity Relationship Sudden infant death syndrome Swelling Tubular formation Vacuole Vesicle angiogenesis base capillary clinically relevant common treatment design extracellular human disease in vivo inhibitor/antagonist insight membrane activity novel strategies prenatal response retinal angiogenesis two-dimensional

项目摘要

DESCRIPTION (provided by applicant): Angiogenesis, the process that new blood vessels form from existing vessels, is a critical process in development and response to environment and disease. Alterations in vascular development and angiogenesis play important roles in many diverse disease including diabetes, coronary artery disease, stroke, and cancer. More complete understanding of the mechanisms leading to appropriately controlled angiogenesis may lead to new approaches for prevention and/or treatment of these common debilitating diseases. Capillary tubules form from endothelial cells by a process called "cell-hollowing" tubulogenesis, which involves formation and fusion of intracellular vesicles to form a large intracellular vacuole that eventually becomes the extracellular lumen of the tubule. CLIC proteins are a family of chloride channel proteins which largely reside in intracellular membranes. Chloride permeability has long been recognized to play a role in intracellular membrane traffic but the specific proteins responsible for individual chloride conductance of intracellular membranes is still largely unknown. Recently, a CLIC protein has been shown to be essential for a specific cell-hollowing tubulogenic process in C. elegans and the family member CLIC4 has been implicated in tubulogenesis in vitro of mammalian endothelial cells. We have recently generated and characterized mice in which the gene for CLIC4 has been disrupted. Preliminary data from these mice provide startling and exciting new evidence that CLIC4 is indeed involved in angiogenesis. Our hypothesis is that CLIC4 plays a critical role in angiogenesis, perhaps by providing the chloride conductance necessary for the orderly membrane traffic and membrane fusion steps involved in cell-hollowing tubulogenesis of endothelial cells. We propose to: 1) Study CLIC4 (-/-) mice for abnormalities in vascular development and response to angiogenic stimuli; 2) Identify sequences and motifs within CLIC4 that are necessary for its function in cell-hollowing tubulogenesis; and 3) Investigate transport properties of membranes derived from cells undergoing tubulogenesis for an activity attributable to CLIC4 and explore how that effects tubulogenesis. The proposal thus is a hypothesis-driven basis science project that uses novel approaches and reagents to address a recently-identified key step in angiogenesis about which little is currently known mechanistically. The results will have clear clinical relevance to the many diseases in which angiogenesis plays a part.

描述(申请人提供)：血管生成，即从现有血管形成新血管的过程，是发育和对环境和疾病做出反应的关键过程。血管发育和血管生成的改变在许多不同的疾病中起着重要的作用，包括糖尿病、冠状动脉疾病、中风和癌症。更全面地了解导致适当控制血管生成的机制可能会为预防和/或治疗这些常见的衰弱疾病提供新的方法。毛细管是由内皮细胞通过一种称为“细胞空化”的过程形成的，这一过程涉及细胞内小泡的形成和融合，形成一个大的细胞内空泡，最终成为小管的细胞外腔。CLIC蛋白是一个氯通道蛋白家族，主要存在于细胞膜上。长期以来，氯离子通透性在细胞内膜运输中起着重要的作用，但负责单个细胞内膜氯离子电导的特定蛋白在很大程度上仍不清楚。最近，研究表明CLIC蛋白在线虫特定的细胞中空小管形成过程中是必不可少的，而CLIC4家族成员参与了哺乳动物血管内皮细胞的体外小管形成。我们最近培育出了CLIC4基因被破坏的小鼠，并对其进行了鉴定。来自这些小鼠的初步数据提供了令人震惊和令人兴奋的新证据，表明CLIC4确实参与了血管生成。我们的假设是，CLIC4在血管生成中发挥关键作用，可能是通过提供有序的膜运输和膜融合步骤所必需的氯电导，这些步骤涉及内皮细胞的中空小管形成。我们建议：1)研究CLIC4(-/-)小鼠的血管发育异常和对血管生成刺激的反应；2)确定CLIC4内对细胞中空小管发生功能所必需的序列和基序；3)研究小管发生过程中细胞膜的运输特性，以确定CLIC4的活动如何影响小管形成。因此，该提案是一个假设驱动的基础科学项目，它使用新的方法和试剂来解决最近确定的血管生成的关键步骤，目前对此机制知之甚少。这一结果将对许多血管生成起作用的疾病具有明确的临床相关性。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Aberrant chloride intracellular channel 4 expression contributes to endothelial dysfunction in pulmonary arterial hypertension.

DOI：
10.1161/circulationaha.113.006797
发表时间：
2014-04-29
期刊：
Circulation
影响因子：
37.8
作者：
Wojciak-Stothard B;Abdul-Salam VB;Lao KH;Tsang H;Irwin DC;Lisk C;Loomis Z;Stenmark KR;Edwards JC;Yuspa SH;Howard LS;Edwards RJ;Rhodes CJ;Gibbs JS;Wharton J;Zhao L;Wilkins MR
通讯作者：
Wilkins MR

Chloride channels of intracellular membranes.