Diabetic foot ulcers are the primary etiology resulting in over 1,000 amputations per week in the United States. The cost of these ulcers is measured in the billions, and the morbidity is excessive. No patient therapy is currently available that significantly stimulates angiogenesis in a wound. The goal of this Mentored Clinical Scientist Development Award is to allow the Principal Investigator to obtain the expertise necessary to develop, coordinate and translate laboratory findings on gene therapy, growth factors, angiogenesis, and diabetes into practical clinical applications for developing new local angiogenic gene therapy for treatment of diabetic foot ulcers. Since angiogenesis maintains a critical role in wound healing, an angiogenic molecule such as Vascular Endothelial Growth Factor (VEGF) may provide an effective treatment either alone or as part of combination therapy for patients with diabetic wounds. Systemic therapy may, however, be limited by side effects such as possible induction of retinopathy. The primary objective is to determine the minimal dose of the angiogenic molecule, VEGF delivered by either adenovirus (ADV), or recombinant VEGF, which will result in statistically significant acceleration of time to 100% closure in experimental diabetic wounds. Furthermore, insights into the mechanism by which VEGF exerts its acceleration of healing in experimental diabetic ulcers will be gained. The role of collagen synthesis and angiogenesis synthesis in the closure rates of diabetic ulcers will be delineated after treatment with VEGF. Any toxicity will be established by evaluating the: a) local inflammatory response at the wound site after VEGF therapy, b) the systemic absorption of VEGF after VEGF therapy, and c) the effect on distant organs that may be particularly susceptible to VEGF therapy. If VEGF therapy fails to be safe or effective, alternative methods of growth factor release have been proposed, e.g., a polymer delivery system. The major goal of the research will be to ascertain that local angiogenic gene therapy with selected growth factors is safe and has minimal system toxicity. Working in an academic environment during the period of this award, the PI will continue his involvement in the clinical and basic research training and teaching of medical students and housestaff on diabetic foot ulcers. Support from this proposal will allow the applicant to use knowledge from the fields of gene therapy, angiogenesis and wound healing to develop a safe angiogenic gene therapy for diabetic foot ulcers.
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