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Genetic and functional analysis on the role of the novel homologues of angiotensin converting enzyme (ACE) in angiogenesis/blood vessel formation


Inhibition of new blood vessel formation is a promising therapy against cancer, diabetic retinopathy, or rheumatoid arthritis where pathological angiogenesis occurs. However, as shown by the failure of some angiogenesis inhibitors in clinical trials, the m olecular mechanisms of angiogenesis are still elusive and more effective and fine-tuned therapies for angiogenic diseases are awaited. New evidence indicates that angiotensin II, generated by angiotensin converting enzyme (ACE), contributes to the progress ionof diabetic retinopathy and some cancers. The precise role of the renin-angiotensin pathway in angiogensis is unknown. Josef Penninger's laboratory recently identified a novel homologue of ACE, termed ACE-2. In genetic experiments his group showed that ACE2 is a candidate QTL for hypertensions and that loss of ACE2 results in heart failure and decreased heart functions (Crackower et al. Nature 2002). These data provided the first genetic evidence that the renin-angiotensin system has a critical and direc t role in the heart and introduced a novel paradigm for negative regulation of the renin-angiotensin pathway, i.e. ACE2 counterbalances the function of ACE. The goal of this proposal is to identify the role of ACE-family molecules ACE, ACE2, and collectrin and their vasoactive peptide substrates such as angiotensin II in angiogenesis and to develop novel therapeutic strategies to modulate new blood vessel formation in disease. We propose to investigate angiogenesis in knockout mice of ACE, ACE2 and collectr in as well as mice that have mutations in the ACE/ACE2 substrates angiotensinogen, apelin, and bradykinin using murine angiogenesis models. We hypothesize that adult angiogenesis in mammals is conserved in primitive vascular development in fruitfly, since a P-element mutation associated with the Drosophila ACE/ACE2 homologue ACER results in defective heart tube formation. To elucidate yet unknown substrate peptides and/or #'

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