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

描述（由申请人提供）：不受控制的毛细血管形成是许多疾病的主要促成因素，包括癌症、糖尿病性视网膜病变和湿性黄斑变性-所有这些疾病在一般人群中表现出高发病率，并且具有有限的长期治疗选择。最近使用抑制血管形成的药物贝伐单抗（Avastin）的临床试验证明，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改善之一。虽然许多靶向病变组织中血管形成的药物表现出有限的副作用，并已被证明可以延缓疾病进展，但仍然没有治愈这些疾病的方法，并且新血管靶点的鉴定可能会导致更有效的治疗方法。该项目的长期目标是发现控制血管形成的机制，作为开发上级疗法的先决条件，以减轻涉及异常血管生成的疾病，如癌症和眼部疾病。病变组织中新血管的形成依赖于一种称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ROCK 2的蛋白，该蛋白在血管壁细胞（内皮细胞[EC]）中表达;然而，ROCK 2控制这一过程的具体机制在很大程度上是未知的。为了更好地确定ROCK 2是否是针对患病组织中血管形成的合理药物靶标，已经提出了以下实验：#1确定ROCK 2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-所有新血管形成所必需的过程，（目的#2）鉴定由ROCK 2调节的EC结构中的形态学变化，和（目的#3）确定ROCK 2在控制参与新血管形成的基因表达中的重要性。实现本提案中概述的具体目标将为确定ROCK 2是否是许多疾病中不受控制的毛细血管形成的适当和潜在有效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.