The primary aim of this study is to develop novel molecular imaging methodologies to visualize and measure the expression and activity of tyrosine kinase growth factor receptor in vivo. The Met tyrosine kinase growth factor receptor and its ligand hepatocyte growth factor/scatter factor (HGF/SF), important genes in development, tumorigenicity and metastasis, will serve as a model. We propose to evaluate and image the expression and activity of Met and HGF/SF both at the cellular and organism levels by comparing different imaging modalities (confocal microscopy, MRI, PET and ultrasound) to conventional biochemical analysis. Using imaging techniques with fluorescence and/or luminescence tagged Met and HGF/SF we will directly image and measure the presence of these important molecules in normal tissues and tumors. We will, in parallel, perform direct analysis of Met and HGF/SF in normal and tumor tissue by IP and western blot. We will use this information together with molecular imaging in animal models to evaluate and quantify the efficacy of both standard therapeutics (e.g. drugs, radiation and hormones) and neutralizing antibodies to Met and HGF/SF for potential utilization of imaging technologies in human cancer.
Specific Aims : 1. We will measure Met interaction with its ligand (HGF/SF) and its signal transduction substrates at the sub-cellular level using fluorescence tagged proteins. 2. We will develop molecular imaging techniques to determine in animal models, the presence of Met and HGF/SF, using fluorescence tagged proteins in xenograph tumors and in transgenic and """"""""knocked in"""""""" animals. These animals models should allow real-time observation of Met mediated tumorigenesis. 3) We will develop non-invasive """"""""indirect"""""""" metabolic molecular imaging methodologies for assessing Met activity at the organism level and in tissues as well as during tumor formation. We wiill be measured real-time in vivo using imaging modalities of MRI-BOLD, MRS,PET and Doppler ultrasound to assess their diagnostic potential. 4) We will quantify and characterize the combinatorial effect of a variety of Met signal transduction inhibitors in vivo on tumors and metastasis. The effects will be studied in animal models using direct and indirect molecular imaging modalities during therapy.
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