Hypoxia plays important roles in a host of biological processes. In cancer development, it is closely associated with the initiation and regulation of angiogenesis. Hypoxia is also an important factor in responses of tumor to various therapeutics such radiotherapy and chemotherapy. In addition, there is increasing evidence pointing to the negative correlation of tumor hypoxia to patient prognosis. Therefore, there is an urgent need to develop better approaches to study hypoxia in vivo. The goals of this project is to evaluate the feasibility of establishing a transgenic strain of mouse the will allow molecular imaging of tumor hypoxia non-invasively. We will have the following specific aims: 1) To establish transgenic mice with two reporter genes: firefly luciferase gene and a green fluorescence protein(GFP) gene, the reporter genes will be placed under a control of a hypoxia responsive promoter that has shown excellent hypoxia-inducibility in tissue-cultured cells. The expectation is that the luciferase gene will allow the non-invasive imaging of hypoxia in various tissues. 2) To image hypoxia through reporter gene expression in spontaneously arising prostate cancer models. The model will be derived by cross-breeding of our hypoxic-reporter transgenic mice with the TRAMP transgenic mice that will develop prostate tumor spontaneously. 3) To image hypoxia at the earliest stages of tumor growth. This will be achieved by use of a novel dorsal skin-fold window chamber in combination with the newly developed hypoxia reporter mouse and fluorescent protein expressing tumor cells. At the end of the study, we hope we can establish the feasibility of generating transgenic animals that will allow us to image tumor hypoxia in a non-invasive and serial fashion. These models can potentially advance our understanding tumor hypoxia and its role in tumor development significantly. The model will may also have potential use in the study of many other physiological/pathological conditions where hypoxia is important.
| Li, Fang; Huang, Qian; Chen, Jiang et al. (2010) Apoptotic cells activate the ""phoenix rising"" pathway to promote wound healing and tissue regeneration. Sci Signal 3:ra13 |
