Local Angiogenic Therapy for Diabetic Ulcers

描述（由申请人提供） 糖尿病足溃疡是导致超过1000例糖尿病足的主要病因。 在美国，每周截肢。这些溃疡的成本是衡量 数以亿计，而且发病率过高。没有病人治疗是 目前可获得的显著刺激伤口中血管生成的药物。的 这个指导临床科学家发展奖的目标是让 主要研究者获得开发、协调 并将基因治疗、生长因子、 血管生成和糖尿病的临床应用， 新的局部血管生成基因疗法治疗糖尿病足溃疡。以来 血管生成在伤口愈合中起关键作用， 如血管内皮生长因子（VEGF）可以提供有效的 单独治疗或作为联合治疗的一部分， 糖尿病伤口然而，全身治疗可能受到副作用的限制， 可能诱发视网膜病变。主要目标是确定 腺病毒递送的最小剂量的血管生成分子VEGF (ADV)，或重组VEGF，这将导致统计学显著的 加速实验性糖尿病伤口100%闭合的时间。 此外，深入了解VEGF发挥其加速作用的机制， 实验性糖尿病溃疡的愈合。胶原蛋白的作用 合成和血管生成合成在糖尿病溃疡愈合率中的作用 将在用VEGF治疗后描绘。将确定任何毒性 通过评估：a）VEGF治疗后伤口部位的局部炎症反应， B）VEGF治疗后VEGF的全身吸收，和c）VEGF治疗后VEGF的全身吸收。 可能对VEGF治疗特别敏感的远端器官的影响。 如果VEGF治疗不能安全或有效， 已经提出了因子释放，例如，聚合物输送系统。 这项研究的主要目标是确定局部血管生成基因， 用选择的生长因子进行治疗是安全的并且具有最小的系统毒性。 在此奖项期间在学术环境中工作，PI将 继续参与临床和基础研究培训， 医学生和家庭工作人员关于糖尿病足溃疡的教学。支持 将允许申请人使用来自以下领域的知识： 基因治疗、血管生成和伤口愈合，以开发安全的血管生成基因 治疗糖尿病足溃疡。

DESCRIPTION (provided by applicant) 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.