Local Angiogenic Therapy for Diabetic Ulcers

描述(由申请人提供) 糖尿病足溃疡是导致1000多人死亡的主要原因 在美国每周截肢。这些溃疡的成本是经过计算的 数十亿美元，发病率过高。没有病人的治疗是 目前可用于显著刺激伤口血管生成的药物。这个 这个指导临床科学家发展奖的目标是让 首席调查员获得必要的专业知识，以制定、协调 并将实验室关于基因治疗、生长因子、 血管生成和糖尿病进入临床实际应用开发 治疗糖尿病足溃疡的新的局部血管生成基因疗法。自.以来 血管生成在伤口愈合中起着关键作用，这是一种血管生成分子 如血管内皮生长因子(VEGF)可能提供一种有效的 对患有以下疾病的患者进行单独治疗或作为联合治疗的一部分 糖尿病伤口。然而，全身治疗可能会受到副作用的限制，比如 尽可能诱发视网膜病变。主要目标是确定 最小剂量的血管生成分子，由任一腺病毒传递的血管内皮生长因子 (ADV)，或重组血管内皮生长因子，这将导致统计意义上的 加快实验性糖尿病创面100%愈合的时间。 此外，对血管内皮生长因子发挥加速作用的机制的洞察 实验性糖尿病溃疡的愈合率将得到提高。胶原蛋白的作用 合成和血管生成合成与糖尿病溃疡闭合率的关系 将在用血管内皮生长因子治疗后被描绘出来。任何毒性都将被确定 通过评估：a)血管内皮细胞生长因子术后创面的局部炎症反应 治疗，b)血管内皮细胞生长因子治疗后的全身吸收，以及c) 对可能对血管内皮生长因子治疗特别敏感的远处器官的影响。 如果血管内皮生长因子治疗不安全或有效，替代生长方法 已经提出了因子释放，例如聚合物递送系统。 这项研究的主要目标将是确定局部血管生成基因 用选定的生长因子治疗是安全的，系统毒性最小。 在获奖期间，在学术环境中工作，PI将 继续参与临床和基础研究培训并 教授医学生和家政人员有关糖尿病足溃疡的知识。支持 将允许申请者使用以下领域的知识 基因治疗、血管生成和伤口愈合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.