Role of Neuropeptides in Diabetic Foot Problems

描述（由申请人提供）：伤口愈合不良是糖尿病的一个重要临床问题，导致糖尿病足溃疡无法完全愈合，每年有超过75，000例下肢截肢。基于我们广泛的临床工作，我们已经指出了神经病变和缺血的协同病理生理学在创建糖尿病足的受损生物学。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伤口愈合的新动物模型中的作用。目前建议的主要假设是神经肽在伤口愈合中起重要作用，并且由于周围神经病变而缺乏它们，结合糖尿病相关的慢性炎症，导致血管生成和伤口愈合受损。我们的具体目标是：1.为了开发体内糖尿病兔模型，用于研究皮肤伤口愈合和在多种状态存在下愈合失败：仅糖尿病、糖尿病伴周围缺血、糖尿病伴周围神经病变和糖尿病伴周围缺血和神经病变，2.研究P物质和P物质神经激肽受体（NK-1 r）基因敲除（KO）糖尿病和非糖尿病小鼠的伤口愈合过程、细胞因子表达、血管生成和组织氧合。我们还将在外周联合施用NK-1 R、拮抗剂和3后评估野生型小鼠（糖尿病和非糖尿病）中的相同参数。研究神经病变和非神经病变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愈合失败有关。这些研究，从实验室到床边，将极大地推进伤口愈合广泛领域的知识，并将特别导致基础和转化研究数据的发展，这些数据可以导致新的治疗方法的发展，以改善糖尿病伤口愈合 公共卫生相关性：伤口愈合不良是糖尿病的一个重要临床问题，导致糖尿病足溃疡无法完全愈合，每年有超过75，000例下肢截肢。当前提议的主要假设是神经肽（由神经纤维分泌的肽）在伤口愈合中起重要作用，并且由于周围神经病变以及糖尿病相关的慢性炎症而缺乏它们导致血管生成和伤口愈合受损。我们预计，本方案中提出的研究，从实验室到床边，将大大提高我们的知识，并将导致基础和转化研究数据的发展，从而开发新的治疗方法来改善糖尿病伤口愈合。

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.