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Role of Protein Ubiquitination in Angiogenesis

蛋白质泛素化在血管生成中的作用

基本信息

批准号：
7915459
负责人：
Nader Rahimi
金额：
$ 40.22万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-01 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7915459
关键词：
Address Adverse effects Age related macular degeneration Angiogenic Switch Applications Grants Biological Blood Vessels Cells Data Development Diabetic Retinopathy Diagnostic Disease Endothelial Cells Endothelium Equilibrium Eye diseases F Box Domain Goals Human In Vitro Investigation Ligase Malignant Neoplasms Mediating Molecular PLC gamma1 Pathologic Neovascularization Phosphorylation Physiological Processes Play Process Protein Kinase C Protein-Serine-Threonine Kinases Proteins Protocols documentation Receptor Protein-Tyrosine Kinases Recruitment Activity Regulation Rheumatoid Arthritis Ring Finger Domain Role Serine Signal Transduction Site Small Interfering RNA Testing Therapeutic Intervention Time Ubiquitination VEGFR inhibition Vascular Endothelial Growth Factor Receptor-2 Vascular Endothelial Growth Factors angiogenesis antiangiogenesis therapy base combat human disease in vivo neuron development novel public health relevance receptor treatment strategy tumor growth ubiquitin-protein ligase vasculogenesis

项目摘要

DESCRIPTION (provided by applicant): It is becoming increasingly apparent that targeting angiogenesis presents an attractive and certainly wide- ranging therapy for many human diseases ranging from cancer to eye diseases. New pharmacologic therapies to target VEGFR-2 (vascular endothelial growth factor receptor-2) are currently being developed for treatment of several human diseases including, age-related macular degeneration (AMD) and various forms of cancers. It is widely accepted that the angiogenic switch is OFF when the effect of pro-angiogenic molecules such as VEGF and its receptor, VEGFR-2 is balanced by that of anti-angiogenesis molecules, and is ON when the net balance is tipped in favor of angiogenesis. Our recent studies for the first time have identified c-Cbl, ring finger containing ubiquitin E3 ligase as a molecular switch that turns off the angiogenic signaling of VEGFR-2. The goals of this grant application are to investigate role of protein ubiquitination in angiogenesis and the mechanisms involved in this process. In particular, we will investigate role of VEGF-dependent ubiquitination of VEGFR-2, E3 ligases involved in ubiquitination of VEGFR-2, the mechanism by which they are being recruited to VEGFR-2 and sites of ubiquitination will be identified. Moreover, we will address how ubiquitination inhibits PLC-gamma1 activation and investigate its application in angiogenesis. Identification of molecules that negatively regulates VEGFR-2 activation and its signaling partners, thereby targets them for degradation will serve twofold purposes: Unravel the basic mechanisms involved in the negative regulation of angiogenesis. Provide new avenues for development of better and more effective agents to combat angiogenesis-associated diseases. PUBLIC HEALTH RELEVANCE: Angiogenesis, the process by which new blood vessels are formed, is a fundamental pathological condition that contributes to human diseases ranging from diabetic retinopathy and age-related macular degeneration to cancer. Vascular endothelial growth factor (VEGF) and its receptor, VEGFR-2 are responsible for induction of angiogenesis and hence for angiogenesis-associated diseases. Identification of molecules that inhibit the angiogenic signaling of VEGFR-2 will provide new avenues for development of better and more effective agents to combat angiogenesis-associated diseases.

描述(由申请人提供)：越来越明显的是，靶向血管生成为从癌症到眼病的许多人类疾病提供了一种有吸引力的、当然也是广泛的治疗方法。针对VEGFR-2(血管内皮生长因子受体-2)的新的药物疗法目前正在开发，用于治疗几种人类疾病，包括老年性黄斑变性(AMD)和各种形式的癌症。人们普遍认为，当促血管生成分子及其受体VEGFR-2的作用被抗血管生成分子平衡时，血管生成开关关闭，当净平衡倾向于血管生成时，血管生成开关开启。我们最近的研究首次发现c-Cbl，即含有泛素E3连接酶的无名指，是关闭VEGFR-2血管生成信号的分子开关。这项资助申请的目标是研究蛋白质泛素化在血管生成中的作用和这一过程中涉及的机制。特别是，我们将研究依赖血管内皮生长因子的VEGFR-2泛素化的作用，参与VEGFR-2泛素化的E3连接酶，它们被招募到VEGFR-2的机制以及泛素化的位置将被确定。此外，我们将讨论泛素化如何抑制PLC-Gamma1的激活，并研究其在血管生成中的应用。识别负调控VEGFR-2激活的分子及其信号伙伴，从而将它们作为降解的目标，将有两个目的：解开涉及血管生成负调控的基本机制。为开发更好、更有效的抗击血管生成相关疾病的药物提供新的途径。与公共卫生相关：血管生成，即形成新血管的过程，是导致从糖尿病视网膜病变、老年性黄斑变性到癌症等人类疾病的一种基本病理条件。血管内皮生长因子(VEGF)及其受体VEGFR-2参与血管生成的诱导，从而导致血管生成相关疾病。识别抑制VEGFR-2血管生成信号的分子将为开发更好、更有效的药物来对抗血管生成相关疾病提供新的途径。