PRECLINICAL EVALUATION OF INTERMEDIATE ENDPOINTS

大鼠增殖性视网膜病变动物模型的建立 小鼠对缺血诱导的视网膜新生血管的反应 (Smith等人，1994)被认为是一个理想的系统，在其中 量化血管生成。该系统具有良好的特性和高度的 可重复性产生可量化的新生血管反应100% 动物(皮尔斯等人，1995年)。已有研究表明，血管内皮生长因子 视网膜新生血管中表达上调 血管内皮生长因子拮抗剂对其的抑制作用 缺血诱导的新生血管(Aiello等人，1995)。此外 该模型系统还可以用来测量血管内皮生长因子的水平 血管内皮生长因子、血管内皮生长因子受体、Tie 2、E-选择素、 IV型胶原和AC133等，已知在 并在血管生成的不同阶段发挥重要作用。 多种癌症中的血管生成。一种定量RT-PCR模型是 进行标准化和测试，以测量血管生成反应。 本研究的目标是开发一种分子技术(S)来 量化血管生成，这是高度敏感和较少的 与现有的生物检测或染色相比，劳动密集型 并可用于早期监测血管生成的变化 肿瘤损伤。这个项目是一个)开发一个量化的 小鼠增殖性视网膜病变模型中血管生成的检测 以及b)在人类肿瘤模型中验证其敏感性和有效性 系统(S)以及在临床标本中。

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.