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）：血管生成是现有血管形成的新血管形成的过程，是对环境和疾病的发展和反应的关键过程。血管发育和血管生成的改变在许多多种疾病中起着重要作用，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完整理解可能会导致预防和/或治疗这些常见衰弱疾病的新方法。毛细管通过称为“细胞空心”的小管形成的毛细管从内皮细胞形成，该过程涉及细胞内囊泡形成和融合形成大型细胞内液泡，该液泡最终成为小管的细胞外腔。 Clic蛋白是一个氯化物通道蛋白家族，主要驻留在细胞内膜中。长期以来，氯化物的通透性已被认为在细胞内膜流量中起作用，但是负责细胞内膜的氯化物电导的特定蛋白仍然在很大程度上尚不清楚。最近，已证明一种clic蛋白对于秀丽隐杆线虫中特定的细胞空心肾小管生成过程至关重要，而家族成员Clic4已与哺乳动物内皮细胞的体外微管发生有关。我们最近生成和表征了clic4基因的小鼠。这些小鼠的初步数据提供了令人震惊而令人兴奋的新证据，表明Clic4确实参与了血管生成。我们的假设是，CLIC4在血管生成中起着至关重要的作用，也许是提供氯化物的电导率，用于有序的膜交通和膜融合步骤，涉及内皮细胞的细胞空心管造成的肾小管发生。我们建议：1）研究Clic4（ - / - ）小鼠血管发育异常和对血管生成刺激的反应； 2）识别CLIC4内的序列和基序是其在细胞空心肾小管发生中所必需的； 3）研究源自造成clic4的活性的细胞衍生的膜的转运特性，并探索这如何影响肾纤维生成。因此，该提案是一个假设驱动的基础科学项目，该项目使用新颖的方法和试剂来解决最近识别的血管生成的关键步骤，该步骤目前在机械上很少知道哪些很少。结果将与许多作用的许多疾病具有明显的临床相关性。

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

Absence of chloride intracellular channel 4 (CLIC4) predisposes to acute kidney injury but has minimal impact on recovery.