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Regulation of endothelial cell junctions by VEGF and angiopoietin

VEGF 和血管生成素对内皮细胞连接的调节

基本信息

批准号：
9225233
负责人：
Arie Horowitz
金额：
$ 39万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9225233
关键词：
ANGPT1 gene Actins Address Adherens Junction Angiopoietins Atherosclerosis Binding Proteins Blood Vessels Brain Cells Code Cytoplasm Data Dependence Diabetes Mellitus Disease Disease Outcome Drug Targeting Edema Endothelial Cells Extravasation Eye diseases Foundations Gambling Genes Genetic Glioblastoma Goals Guanine Guanine Nucleotide Exchange Factors Guanosine Triphosphate Phosphohydrolases Heart Diseases Integral Membrane Protein Intercellular Junctions Intracranial Hypertension Knowledge Lead Ligands Macular degeneration Maintenance Malignant Neoplasms Malignant neoplasm of brain Mediating Membrane Protein Traffic Microfilaments Modeling Molecular Morbidity - disease rate Mus Myocardial Ischemia Outcome Pathologic Pathology Pathway interactions Pattern Permeability Pharmaceutical Preparations Process Property Proteins Public Health Receptor Protein-Tyrosine Kinases Recruitment Activity Regulation Research Rheumatoid Arthritis Role Scheme Signal Pathway Signal Transduction Solid Stroke TIE-2 Receptor Tertiary Protein Structure Testing Tight Junctions Vascular Endothelial Growth Factors Vascular Permeabilities Vascular System Zebrafish angiogenesis base cell motility cytokine design effective therapy improved outcome in vivo innovation loss of function mouse model novel novel strategies novel therapeutics prevent protein function public health relevance receptor response stem targeted treatment therapeutic target trafficking

项目摘要

DESCRIPTION (provided by applicant): A crucial gap in the understanding of endothelial cell (EC) junction maintenance is the absence of a molecular mechanism to explain how angiopoietin-1 (Ang1) and its receptor, Tie2, stabilize the junctions. Loss of junction integrity i implicated in numerous diseases, including cancer, stroke, diabetes, rheumatoid arthritis, atherosclerosis, cardiac ischemia, and macular degeneration. In such pathologies, vascular endothelial growth factor (VEGF) has a potent disruptive effect on cell junctions and undermines vessel integrity. In contrast, angiopoietin-1 (Ang1) opposes the effect of VEGF and maintains junction integrity. Similar to Ang1, the formin protein mDia has a stabilizing effect on cell junctions, due to its maintenance of the cortical actin ring. We have obtained exciting preliminary results, which support the premise that mDia is an Ang1 effector. Based on these results, our proposal is expected to provide the first detailed account of the antagonistic effects of VEGF and Ang1 on cell junctions. Our central hypothesis is that VEGF and Ang1 regulate EC junctions by determining the spatial pattern of the activities of mDia and Syx (a RhoA-specific guanine exchange factor upstream of mDia) via membrane traffic. We will address this hypothesis by pursuing three specific aims: (1) determining how Ang1 recruits Syx to EC junctions; (2) determining the role of mDia trafficking in Ang1 and VEGF signaling; (3) determining how Syx and mDia regulate Ang1 signaling in a murine model of glioblastoma. To this end, we will use mouse and zebrafish loss-of-function models of several of the genes relevant to these pathways. The potential contribution of this study is significant because it will advance the field conceptually by integrating VEGF and Ang1 signaling into a coherent regulatory mechanism of vessel permeability. This will have a lasting effect on the general understanding of cell-cell junctions. A consequence of the poor knowledge of Ang1 regulation of cell junctions is the scarcity of drugs to target the Ang1 signaling pathway. This putative pathway, leading from Ang1/Tie2 to mDia and to the stabilization of endothelial cell junctions, implicates several proteins that have not been considered before as drug targets. The elucidation of this signaling pathway will provide, therefore, a solid foundation for the design of new therapies to prevent vessel leakage in pathological conditions. As a principal outcome, we will define key checkpoints that will allow us to selectively control VEGF vs. Ang1/Tie2 mediated angiogenesis. These features constitute the potential translational significance of our proposed research. The proposed research is innovative in that it will reveal a novel signaling pathway to explain how Ang1 stabilizes EC junctions, and will incorporate membrane traffic as a novel component of angiogenesis.

描述（由申请方提供）：在内皮细胞（EC）连接维持的理解中存在一个关键的空白，即缺乏解释血管生成素-1（Ang 1）及其受体Tie 2如何稳定连接的分子机制。连接完整性的丧失涉及许多疾病，包括癌症、中风、糖尿病、类风湿性关节炎、动脉粥样硬化、心脏缺血和黄斑变性。在这些病理中，血管内皮生长因子（VEGF）对细胞连接具有强有力的破坏作用，并破坏血管完整性。相反，血管生成素-1（Ang 1）对抗VEGF的作用并维持连接的完整性。与Ang 1类似，由于其维持皮质肌动蛋白环，所以mDia蛋白对细胞连接具有稳定作用。我们已经获得了令人兴奋的初步结果，这支持的前提下，mDia是一个血管生成素1效应。基于这些结果，我们的建议有望提供对抗效应的第一个详细说明血管内皮生长因子和血管生成素1的表达。我们的中心假设是VEGF和Ang 1通过膜交通确定mDia和Syx（mDia上游的RhoA特异性鸟嘌呤交换因子）活动的空间模式来调节EC连接。我们将通过追求三个具体目标来解决这一假设：（1）确定Ang 1如何将Syx招募到EC连接处;（2）确定mDia运输在Ang 1和VEGF信号传导中的作用;（3）确定Syx和mDia如何在胶质母细胞瘤小鼠模型中调节Ang 1信号传导。为此，我们将使用与这些途径相关的几个基因的小鼠和斑马鱼功能丧失模型。这项研究的潜在贡献是重要的，因为它将通过将VEGF和Ang 1信号传导整合到血管渗透性的连贯调节机制中，在概念上推进该领域。这将对细胞间连接的一般理解产生持久的影响。Ang 1调节细胞连接的知识贫乏的后果是缺乏靶向Ang 1信号通路的药物。这种推定的途径，导致从Ang 1/Tie 2的mDia和稳定的内皮细胞连接，牵连到几个蛋白质，以前没有被认为是药物的目标。因此，阐明这一信号通路将为设计新的治疗方法，以防止在病理条件下的血管渗漏。作为主要结果，我们将定义关键检查点，使我们能够选择性地控制VEGF与Ang 1/Tie 2介导的血管生成。这些特征构成了我们所提出的研究的潜在翻译意义。拟议的研究是创新的，因为它将揭示一种新的信号通路来解释Ang 1如何稳定EC连接，并将膜交通作为血管生成的一种新成分。