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：
7464819
负责人：
Nader Rahimi
金额：
$ 40.63万
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 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7464819
关键词：
Address Adverse effects Age related macular degeneration Angiogenic Switch Appendix Applications Grants Biological Blood Vessels Cells Condition Data Degenerative polyarthritis Development Diabetic Retinopathy Diagnostic Disease Endothelial Cells Endothelium Equilibrium Eye diseases F Box Domain Goals Human In Vitro Investigation Ligase Malignant Neoplasms Mediating Molecular Neurons PLC gamma1 Pathologic Neovascularization Phosphorylation Physiological Processes Play Process Protein Kinase C Protein-Serine-Threonine Kinases Proteins Protocols documentation Public Health Purpose Range 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 human disease in vivo novel receptor 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，靶向血管生成为许多人类疾病提供了一种吸引人的，肯定是广泛的疗法，从癌症到眼部疾病。目前正在开发针对VEGFR-2（血管内皮生长因子受体2）的新药理疗法（血管内皮生长因子受体2），用于治疗多种人类疾病，包括与年龄相关的黄斑变性（AMD）和各种形式的癌症。人们普遍认为，当促血管生成分子（如VEGF及其受体）的作用与抗血管生成分子的效果保持平衡，并且当净平衡倾斜以支持血管生成时，VEGFR-2的效果是关闭的。我们最近的第一次研究确定了含有泛素E3连接酶的C-CBL手指，是一种分子开关，它关闭了VEGFR-2的血管生成信号传导。该赠款应用的目标是研究蛋白质泛素化在血管生成中的作用以及此过程中涉及的机制。特别是，我们将研究VEGFR-2的VEGF依赖性泛素化的作用，涉及VEGFR-2泛素化的E3连接酶，将确定将它们募集到VEGFR-2和泛素化位置的机制。此外，我们将解决泛素化如何抑制PLC-GAMMA1激活并研究其在血管生成中的应用。鉴定对VEGFR-2激活及其信号伴侣负调节的分子，因此将它们靶向降解将有双重目的：揭示涉及血管生成负调节的基本机制。为开发更好，更有效的药物来打击血管生成相关疾病提供新的途径。公共卫生相关性：血管生成是形成新血管的过程，是一种基本的病理状况，有助于人类疾病，从糖尿病性视网膜病和与年龄相关的黄斑变性到癌症。血管内皮生长因子（VEGF）及其受体VEGFR-2负责诱导血管生成，因此血管生成相关疾病。抑制VEGFR-2血管生成信号传导的分子的鉴定将为开发更好，更有效的药物以打击血管生成相关疾病。