PRECLINICAL EVALUATION OF INTERMEDIATE ENDPOINTS

增殖性视网膜病变的实验模型， 对缺血诱导的小鼠视网膜新生血管的反应 （Smith等人，1994）是一个理想的系统， 定量血管生成。 该系统具有良好的特性， 可重现，100%产生可量化的新生血管反应 （Pierce et al，1995）。 研究表明，VEGF 在视网膜新生血管形成过程中表达上调， VEGF拮抗剂对其的抑制导致 缺血诱导的新血管形成（Aiello等，1995）。 除了 VEGF，该模型系统也可用于测量 几种基因如VEGF、VEGFR、Tie 2、E-选择素、 胶原蛋白IV和AC 133等，已知其在哺乳动物中上调。 血管生成，并发挥重要作用，在各个阶段， 多种癌症中的血管生成。 定量RT-PCR模型是 被标准化和测试以测量血管生成反应。 这项研究的目标是开发一种分子技术， 定量血管生成，这是高度敏感， 比现有的生物测定或染色更劳动密集 并且可以用于监测早期的血管生成变化。 肿瘤性病变 该项目是a）开发一个定量的 增殖性视网膜病小鼠模型中的血管生成测定 和B）验证其在人肿瘤模型中的灵敏度和有用性 系统以及临床标本中。

An experimental model of proliferative retinopathy produced in response to ischemia-induced retinal neovascularization in mice (Smith et al, 1994) lends itself as an ideal system in which to quantitate angiogenesis. The system is well characterized and highly reproducible generating a quantifiable neovascular response in 100% of animals (Pierce et al, 1995). It has been shown that VEGF expression is upregulated during retinal neovascularization and that its inhibition by VEGF antagonists leads to suppression of ischemia-induced neovascularization (Aiello et al, 1995). Besides VEGF, this model system can also be used to measure the levels of expression of several genes such as VEGF, VEGFR, Tie 2, E-Selectin, Collagen IV, and AC133 etc, which are known to be upregulated during angiogenesis and play an essential role during various phases of angiogenesis in multiple cancers. A quantitative RT-PCR model is being standardized and tested to measure the angiogenic response . The goal of the study is to develop a molecular technique(s) to quantitate angiogenesis, which is highly sensitive and less labor-intensive than the existing biological assays or staining procedures and can be used to monitor angiogenic changes in early neoplastic lesions. This project is a) developing a quantitative angiogenesis assay in the mouse model of proliferative retinopathy and b) validating its sensitivity and usefulness in human tumor model system(s) as well as in clinical specimens.