Modulation of Angiogenesis by Regulated Dimerization

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DESCRIPTION (Applicant's abstract): The uninterrupted delivery of oxygen and nutrients is essential for the growth, maintenance and survival of body tissues. In response to injury, inflammation, or hypoxic stress, the body typically responds with an upregulation of angiogenic growth factors, which in turn stimulate angiogenesis, the growth of new blood vessels. Disruptions in the balance between tissue injury and this compensatory neovascularization is directly related to the pathological outcomes associated with myocardial infarction, diabetic vascular disease, vascular occlusive disease, and aging. Direct revascularization therapy is an emerging mode of therapy for treating inadequately perfused tissues, essentially by augmentation of the normal angiogenic response. This has been done using the delivery of angiogenic growth factors such as VEOF directly to the tissue in situ, or the delivery of circulating endothelial progenitor cells (EPC), which have been expanded ex vivo, and which home to the sites of tissue hypoxia and enhance the naturally occurring angiogenic response. This R21 proposal is directed at the exploration and development of an alternate approach: the delivery of a VEGF-receptor that has been modified to respond to a bioactive, small molecule drug, which is a chemical inducer of dimerization (CID), and activates the receptor in a manner independent of VEGF. The development of this system will allow pharmacological regulation of a directed angiogenic response, and combined with EPC modes of therapy, would have the capacity to provide exquisite temporal and spatial control over induced therapeutic angiogenesis. In addition, the development of this system provides a critical experimental platform for the performance of structure-function studies of the VEGF receptors, a prerequisite for understanding angiogenesis at the cell and molecular level.