Role of Protein Ubiquitination in Angiogenesis

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且肯定广泛的治疗方法.目前正在开发靶向VEGFR-2（血管内皮生长因子受体-2）的新的药理学疗法，用于治疗几种人类疾病，包括年龄相关性黄斑变性（AMD）和各种形式的癌症。广泛接受的是，当促血管生成分子如VEGF及其受体VEGFR-2的作用被抗血管生成分子的作用平衡时，血管生成开关关闭，而当净平衡倾向于血管生成时，血管生成开关打开。我们最近的研究首次鉴定了c-Cbl，含有泛素E3连接酶的环指，作为关闭VEGFR-2的血管生成信号传导的分子开关。 这项研究的目的是研究蛋白质泛素化在血管生成中的作用以及参与这一过程的机制。特别是，我们将研究VEGFR-2的VEGF依赖性泛素化的作用，E3连接酶参与VEGFR-2的泛素化，它们被招募到VEGFR-2的机制和泛素化位点将被确定。此外，我们将讨论泛素化如何抑制PLC-γ 1激活，并研究其在血管生成中的应用。 鉴定负调节VEGFR-2活化及其信号传导伙伴的分子，从而靶向它们进行降解，将达到双重目的：揭示血管生成负调节的基本机制。为开发更好和更有效的药物以对抗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，是导致从糖尿病视网膜病变和年龄相关性黄斑变性到癌症的人类疾病的基本病理状况。血管内皮生长因子（VEGF）及其受体VEGFR-2负责诱导血管生成并因此导致血管生成相关疾病。鉴定抑制VEGFR-2的血管生成信号传导的分子将为开发更好和更有效的药物以对抗血管生成相关疾病提供新的途径。

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.