DOCK4 regulation of small GTPases in vascular permeability

DOCK4 对小 GTP 酶对血管通透性的调节

• 批准号: 8066412
• 负责人: Francisco Cullere
• 金额: $ 12.93万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-14 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8066412
• 关键词: Abbreviations; Actin-Binding Protein; Actins; Adherens Junction; Agonist; Area; Atopic Dermatitis; Biology; Blood Vessels; Cell physiology; Cells; Chairperson; Contact Dermatitis; Cytoskeleton; DNA Sequence Rearrangement; Data; Development; Disease; Edema; Endothelial Cells; Endothelium; Exhibits; Extravasation; Family; Functional disorder; G Protein-Coupled Receptor Genes; G-Protein-Coupled Receptors; GTPase-Activating Proteins; Goals; Guanine; Guanine Nucleotide Exchange Factors; Guanosine Triphosphate Phosphohydrolases; Health; Heart; Human; Immune response; In Vitro; Injury; Kidney; Knowledge; Lead; Lung; Lysophospholipids; MYLK gene; Mediating; Mentors; Molecular; Monomeric GTP-Binding Proteins; Morbidity - disease rate; Mus; Myosin Light Chain Kinase; Pathology; Pathway interactions; Permeability; Phenotype; Phosphorylation; Physiological; Play; Process; Protein Family; Proteins; Proteomics; Regulation; Research; Rheumatism; Role; Signal Pathway; Skin; Small Interfering RNA; Tissues; Training; Training Programs; Umbilical vein; Vascular Permeabilities; Work; angiogenesis; base; body system; heat injury; human EMS1 protein; human tissue; in vivo; in vivo Model; insight; knock-down; lipid mediator; lysophosphatidic acid; mortality; mutant; novel; osteosarcoma; overexpression; response; rho; skills; skin disorder; sphingosine 1-phosphate; therapeutic target; vascular inflammation

DESCRIPTION (provided by applicant): The objective of this K01 application is to provide a 5 yr training program in vascular biology that allows the PI to acquire essential skills and knowledge to explore the mechanism(s) of endothelial dependent vascular permeability. This represents a new area of research for the PI. The Pi's scientific development will be mentored by Dr. Tanya Mayadas, a recognized leader in the field of vascular inflammation The work will be conducted in the Vascular Research Division which is led by Dr. Michael Gymboree, Chairman of Pathology, who has done pioneering work in elucidating the role of the endothelium in health and disease. The overall goal of this training is to provide the PI the necessary expertise to lead an independent academic research group in the area of vascular biology that is proposed in this application. The regulation of vascular permeability is important to elicit an efficient immune response while maintaining vascular integrity. Its dysregulation is associated with morbidity and mortality in diseases in many organs systems. In the skin, thermal injury, atopic and contact dermatitis are associated with edema which exacerbates these conditions. The goal of this project is to define mechanisms of endothelial barrier function regulated by the very recently identified exchange factor for the Rho and Rap family of GTPases, DOCK4 which directs adherens junction formation in osteosarcoma cells through activation of Rap1. Preliminary data shows robust DOCK4 expression in human umbilical vein endothelial cells and in the endothelium of normal human heart and kidney tissue. In addition, DOCK4 was regulated by endothelial barrier inducing agonists, and its deficiency resulted in changes in the actin cytoskeleton and an increase in endothelial permeability. This proposal is based on the hypothesis that DOCK4 regulation of Rap and Rac GTPases regulates junction remodeling in endothelial cells. The aims will characterize molecular pathways that regulate DOCK4 function and elucidate its downstream targets in endothelial cells and identify the endothelial phenotypes dependent on this protein using in vitro approaches and in vivo models. Results from this work should aid in understanding how endothelial cell barrier function is regulated. We anticipate that this will provide insights into the mechanisms of endothelial dysfunction and tissue injury in skin disorders and rheumatic diseases and identify possible therapeutic targets for treatment of these conditions.

描述（由申请人提供）：本K01申请的目的是提供一个为期5年的血管生物学培训项目，使PI获得探索内皮依赖性血管通透性机制的基本技能和知识。这是PI的一个新的研究领域。Pi的科学发展将由Tanya Mayadas博士指导，他是血管炎症领域公认的领导者。这项工作将在血管研究部门进行，该部门由病理学主席Michael Gymboree博士领导，他在阐明内皮在健康和疾病中的作用方面做了开创性的工作。本培训的总体目标是为PI提供必要的专业知识，以领导本申请中提出的血管生物学领域的独立学术研究小组。血管通透性的调节对于在维持血管完整性的同时引发有效的免疫应答是重要的。它的失调与许多器官系统疾病的发病率和死亡率有关。在皮肤中，热损伤、特应性和接触性皮炎与加重这些病症的水肿相关。本项目的目标是确定最近发现的Rho和Rap家族GTP酶的交换因子DOCK 4调节内皮屏障功能的机制，DOCK 4通过激活Rap1指导骨肉瘤细胞中粘附连接的形成。初步数据显示，在人脐静脉内皮细胞和正常人心脏和肾脏组织的内皮中，DOCK 4表达稳健。此外，DOCK 4由内皮屏障诱导激动剂调节，其缺乏导致肌动蛋白细胞骨架的变化和内皮通透性的增加。这一提议是基于这样的假设，即Rap和Rac GTP酶的DOCK 4调节调节内皮细胞中的连接重塑。这些目标将表征调节DOCK 4功能的分子途径，阐明其在内皮细胞中的下游靶点，并使用体外方法和体内模型鉴定依赖于该蛋白的内皮表型。这项工作的结果应有助于了解内皮细胞屏障功能是如何调节的。我们预计，这将提供深入了解皮肤病和风湿性疾病的内皮功能障碍和组织损伤的机制，并确定治疗这些疾病的可能的治疗靶点。