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（由申请人提供）：血管生成，即从现有血管形成新血管的过程，是发育以及对环境和疾病的反应的关键过程。血管发育和血管生成的改变在许多不同的疾病中发挥着重要作用，包括糖尿病、冠状动脉疾病、中风和癌症。对导致适当控制血管生成的机制的更全面理解可能会带来预防和/或治疗这些常见衰弱疾病的新方法。毛细管由内皮细胞通过称为“细胞空心”的肾小管发生过程形成，该过程涉及细胞内囊泡的形成和融合，形成一个大的细胞内液泡，最终成为毛细管的细胞外腔。 CLIC 蛋白是氯离子通道蛋白家族，主要存在于细胞内膜中。长期以来，人们一直认为氯离子渗透性在细胞内膜运输中发挥作用，但负责细胞内膜个体氯离子电导的特定蛋白质仍然很大程度上未知。最近，CLIC 蛋白已被证明对于秀丽隐杆线虫中特定的细胞空心管形成过程至关重要，并且家族成员 CLIC4 与哺乳动物内皮细胞的体外管形成有关。我们最近生成并鉴定了 CLIC4 基因已被破坏的小鼠。来自这些小鼠的初步数据提供了令人惊讶且令人兴奋的新证据，表明 CLIC4 确实参与血管生成。我们的假设是 CLIC4 在血管生成中发挥着关键作用，可能是通过提供内皮细胞的细胞空心管生成中涉及的有序膜运输和膜融合步骤所需的氯离子电导来实现的。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) 鉴定 CLIC4 内的序列和基序，这些序列和基序对于其在细胞空心管发生中的功能是必需的； 3) 研究来自经历肾小管发生的细胞的膜的转运特性，以了解 CLIC4 的活性，并探讨其如何影响肾小管发生。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发现的血管生成的关键步骤，而目前对其机制知之甚少。结果将与血管生成参与的许多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）

Chloride channels of intracellular membranes.

细胞内膜的氯离子通道。

DOI：
发表时间：
2010-05-17
期刊：
影响因子：
3.5
作者：
Edwards, John C;Kahl, Christina R
通讯作者：
Kahl, Christina R

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

异常的氯离子细胞内通道 4 表达导致肺动脉高压的内皮功能障碍。

DOI：
发表时间：
2014-04-29
期刊：
影响因子：
37.8
作者：
Wojciak;Abdul;Lao, Ka Hou;Tsang, Hilda;Irwin, David C;Lisk, Christina;Loomis, Zoe;Stenmark, Kurt R;Edwards, John C;Yuspa, Stuart H;Howard, Luke S;Edwards, Robert J;Rhodes, Christopher J;Gibbs, J Simon R;Whart
通讯作者：
Whart

Apolipoprotein L1 confers pH-switchable ion permeability to phospholipid vesicles.

载脂蛋白 L1 赋予磷脂囊泡 pH 可切换的离子渗透性。