The Role of LEF/TCF Proteins in Vessel Formation

Many widespread and life-threatening diseases display pathologic angiogenesis. Excess or deficiency in the formation of new blood vessels by angiogenesis can be the hallmark of these diseases. The main example of pathologic angiogenesis is the high vascularization of nearly all malignant tumors and this is one of the factors important for the development of cancer. Inhibition of tumor angiogenesis is therefore likely to become a major part of cancer therapy in the future. On the other side are the ischemic diseases, when a deficiency in vascularization and supply with oxygen and nutrients leads to tissue necrosis. In this case the stimulation of neovascularization, e.g. in the affected heart myocardium following infarct, could prevent further tissue necrosis and promote tissue regeneration. In addition, angiogenesis plays an important role for several cardiovascular diseases including atherosclerosis and thromboses. The proposed project will consist of the following project parts leading to the development of therapeutic strategies: 1) the investigation of the regulatory mechanisms of angiogenesis at the molecular level, 2) the role of incorporation of bone marrow progenitor cells in newly formed vessels, 3) the identification of novel potential target molecules for the modulation of angiogenesis, 4) the relevance of individual signaling pathways and target molecules for certain diseases, 5) the development of cell and gene therapies and 6) their preclinical evaluation in animal disease models. The primary objectives will be to i) inhibit tumor growth and metastasis and ii) to trigger neovascularization and regeneration of damaged tissue following heart infarct. To achieve these goals this project will comprise the collaboration of laboratories with complementary expertise from Vienna and Innsbruck and associate groups from Freiburg i.Br. and Zürich. We include experts in molecular cell biology, in experimental cell and gene therapies and in animal models representative for the respective diseases. Furthermore, laboratories experienced in stem cell differentiation and clinicians active in tumor, vessel, and heart surgery and therapy will participate in the project. We expect feed-back on medical needs from the clinicians and the potential future translation of results of this project into clinical practice.