The Role of VEGF-stimulated Rhoa/ROCK2 Signaling in Blood Vessel Formation

描述(申请人提供)：不受控制的毛细血管形成是许多疾病的主要诱因，包括癌症、糖尿病视网膜病变和湿性黄斑变性-所有这些在普通人群中都显示出高发病率，并且长期治疗选择有限。最近使用抑制血管形成的药物贝伐单抗(阿瓦斯丁)的临床试验表明，在转移性结直肠癌患者的随机研究中，有史以来最大的生存率改善之一。虽然许多针对病变组织中血管形成的药物显示出有限的副作用，并已被证明可以延缓疾病的进展，但仍然没有治愈这些疾病的方法，识别新的血管靶点可能会带来更有效的治疗方法。该项目的长期目标是发现控制血管形成的机制，作为开发更好的治疗方法的先决条件，以减轻涉及异常血管生成的疾病，如癌症和眼疾。病变组织中新血管的形成依赖于一种名为血管内皮生长因子(VEGF)的分泌蛋白，部分依赖于其激活一种名为ROCK2的蛋白，该蛋白表达在血管壁细胞(内皮细胞[ECs])中；然而，ROCK2控制这一过程的具体机制在很大程度上尚不清楚。为了更好地确定ROCK2是否是一个可行的药物靶点来对抗疾病组织中的血管形成，提出了下列实验：#1确定ROCK2在EC细胞分裂、迁移、存活以及细胞与细胞和细胞与环境相互作用中的作用--所有这些过程都是新血管形成所必需的，(目的#2)确定ROCK2调控的EC结构的形态变化，以及(目的#3)确定ROCK2在调控参与新血管形成的基因表达方面的重要性。实现本提案中概述的具体目标将为确定ROCK2是否是多种疾病中不受控制的毛细血管形成的适当和潜在有效的靶点提供所需的基础。

DESCRIPTION (provided by applicant): Uncontrolled capillary formation is a major contributor to numerous diseases including cancer, diabetic retinopathy, and wet macular degeneration-all exhibiting a high incidence in the general population and having limited long term treatment options. Recent clinical trials using the drug Bevacizumab (Avastin), which inhibits blood vessel formation, demonstrated one of the largest improvements in survival ever reported in a randomized study of patients with metastatic colorectal cancer. While many drugs targeting blood vessel formation in diseased tissue exhibit limited side effects and have been proven to delay disease progression, there still exists no cure for these diseases, and identification of novel vascular targets could lead to more effective therapeutics. The long term goal of this project is to discover the mechanisms controlling blood vessel formation as a prerequisite to the development of superior therapies to attenuate diseases involving aberrant angiogenesis such as cancer and ocular maladies. New blood vessel formation in diseased tissues is dependent on a secreted protein called vascular endothelial growth factor (VEGF) and, in part, by its activation of a protein called ROCK2 which is expressed in cells lining the walls of blood vessels (endothelial cells [ECs]); however, the specific mechanism by which ROCK2 controls this process is largely unknown. In order to better determine if ROCK2 is a plausible drug target against blood vessel formation in diseased tissue, the following experiments have been proposed: #1 determining the role of ROCK2 in EC cell division, migration, survival, and in cell-to-cell and cell-to-environment interactions-all processes necessary for new blood vessel formation, (Aim #2) identifying morphological changes in EC structure that are regulated by ROCK2, and (Aim #3) determining the importance of ROCK2 in controlling the expression of genes which are involved in new blood vessel formation. Accomplishing the specific aims outlined in this proposal will provide the foundation required to determine if ROCK2 is an appropriate and potentially effective target for uncontrolled capillary formation in numerous diseases.