Role of Neuropeptides in Diabetic Foot Problems

描述(申请人提供)：伤口愈合受损是糖尿病的一个重要临床问题，导致无法完全治愈糖尿病足部溃疡，每年超过75,000例下肢截肢。基于我们广泛的临床工作，我们指出了神经病变和缺血的协同病理生理学在糖尿病足的生物学损害中的作用。在这项提案中，我们计划扩大我们的研究，并进一步评估神经功能障碍在糖尿病创面愈合新动物模型中的作用。目前该方案的主要假设是神经肽在伤口愈合中起重要作用，周围神经病变导致神经肽缺乏，再加上糖尿病相关的慢性炎症，导致血管生成和伤口愈合受损。本研究的主要目的是：1.建立糖尿病动物模型，研究糖尿病、糖尿病合并周围缺血、糖尿病合并周围神经病变、糖尿病合并周围神经病变等多种状态下皮肤创面愈合及不愈合情况；2.观察糖尿病及P物质神经激肽受体(NK-1R)、KO糖尿病及非糖尿病小鼠创面愈合过程、细胞因子表达、血管生成及组织氧合情况。我们还将在野生型小鼠(糖尿病和非糖尿病)外周联合应用NK-1R、拮抗剂和3后评估相同的参数。研究神经性和非神经性糖尿病患者皮肤水平神经肽的表达，并与健康对照组进行比较。我们还将研究神经肽的表达是否与足部溃疡的发展和足部溃疡的治愈失败有关。这些从工作台到床边的研究将极大地促进伤口愈合的广泛领域的知识，并将特别导致基础和转译研究数据的发展，这些数据可以导致开发新的治疗方法来改善糖尿病的伤口愈合。 公共卫生相关性：伤口愈合受损是糖尿病的一个重要临床问题，导致糖尿病足部溃疡无法完全治愈，每年有超过75,000例下肢截肢。目前提出的主要假设是神经肽，即神经纤维分泌的多肽，在伤口愈合中发挥重要作用，周围神经病变导致神经肽缺乏，再加上糖尿病相关的慢性炎症，导致血管生成和伤口愈合受损。我们期望这一方案中提出的从长椅到床边的研究将极大地增强我们的知识，并将导致基础和转译研究数据的发展，从而开发新的治疗方法来改善糖尿病的伤口愈合。

DESCRIPTION (provided by applicant): Impaired wound healing is an important clinical problem in diabetes resulting in failure to completely heal diabetic foot ulcers and more that 75,000 lower extremity amputations annually. Based on our extensive clinical work we have pointed to the synergistic pathophysiology of neuropathy and ischemia in creating the compromised biology of the diabetic foot. In this proposal we plan to expand our studies and further evaluate the role on nerve dysfunction in new animal models of diabetic wound healing. The main hypothesis of the current proposal is that neuropeptides play an important role in wound healing and that the lack of them due to peripheral neuropathy, combined with the diabetes-related chronic inflammation, leads to impaired angiogenesis and wound healing. Our specific aims are: 1. To develop in vivo diabetic rabbit models for investigating cutaneous wound healing and failure to heal in the presence of multiple states: diabetes alone, diabetes with peripheral ischemia, diabetes with peripheral neuropathy, and diabetes with both peripheral ischemia and neuropathy, 2. To evaluate the wound healing progress, cytokine expression, angiogenesis and tissue oxygenation in substance P and substance P neurokinin-receptor (NK-1r), KO diabetic and non-diabetic mice. We will also evaluate the same parameters in wild type mice (diabetic and non diabetic) after combined peripheral administration of NK-1R, antagonist, and 3. To study the expression of neuropeptides at the skin level of neuropathic and non-neuropathic diabetic patients and compare it to healthy control subjects. We will also examine whether the neuropeptide expression is related to the development of foot ulceration and the failure to heal foot ulcers. These studies, from bench to bedside, will greatly advance knowledge in the broad area of wound healing and will specifically result in the development of basic and translational research data that can lead to the development of new therapeutic approaches to improve wound healing in diabetes PUBLIC HEALTH RELEVANCE: Impaired wound healing is an important clinical problem in diabetes and results in failure to completely heal diabetic foot ulcers and more that 75,000 annual lower extremity amputations. The main hypothesis of the current proposal is that neuropeptides, the peptides that are secreted by the nerve fibers, play an important role in wound healing and that the lack of them due to peripheral neuropathy, combined with the diabetes- related chronic inflammation, leads to impaired angiogenesis and wound healing. We expect that the studies proposed in this protocol, from bench to bedside, will considerably enhance our knowledge and will result in the development of both basic and translational research data that can lead to the development of new therapeutical approaches to improve wound healing in diabetes.