ROLE OF THE NEUROLOGIC SYSTEM IN WOUND HEALING

这项建议是为了回应来自 美国国立卫生研究院研究慢性伤口。数以百万计的慢性伤口被观察到 患有感觉神经系统异常的美国人 糖尿病，脊髓损伤，周围血管疾病，以及 衰老。我们提出了一个新的概念，即慢性伤口的频率 不仅与未被发现的创伤有关 去神经皮肤，而是神经肽的减少或缺失 对于正常的组织修复是必不可少的。众所周知，组织修复是 这些人群中的异常会导致发病率、死亡率、时间损失 从工作中，无数天的住院或住院和 数百万美元的医疗保健费用。在此应用程序中，我们将测试 假设：(1)完整的感觉神经系统对 皮肤创面正常愈合(2)慢性创面发展 神经性损伤患者是急性创面缺陷的结果 愈合，(3)神经受损的皮肤的特征是 P物质(SP)、受体(SPR)表达异常， 中性内肽酶(NEP)、神经生长因子(NGF)和/或NGF受体 (NGFR)，以及(4)皮肤完整性和伤口愈合方面的缺陷 通过治疗性替代或调节 皮肤感觉神经系统有缺陷。这些假设将是 通过以下具体目标进行测试：具体目标#1：检查 皮肤SP、SPR和NEP在皮肤中的表达及调控 正常和神经学受损的患者；具体目标2： 检测大鼠皮肤NGF及其受体的表达和调控 正常和神经学受损患者的皮肤；具体目标3： 检查神经系统在皮肤完整性和创伤中的作用 在神经学受损的小鼠模型中的愈合和；特定目标#4至 确定神经性受损患者的皮肤完整性和伤口愈合情况 动物可以通过皮肤神经的调节而扩大 系统。这些多肽将通过原位定位在皮肤中 杂交和/或免疫组织化学及核糖核酸酶定量 保护试验、Northern印迹、RIA、EL ISA和/或生物测定。我们的建议 研究可能导致治疗贫困的新治疗方法 糖尿病和/或糖尿病患者的皮肤完整性和慢性伤口 神经缺陷和皮肤-假体相互作用。这项研究将是 由三组调查人员进行，他们正在进行 合作。旧金山集团在以下方面提供专业知识 具有良好特性试剂的神经肽。西雅图集团提供 具有良好特性的人体伤口组织的伤口愈合专业知识 图书馆和接触慢性不可愈合溃疡患者和 波特兰集团提供皮肤炎方面的专业知识，包括 神经肽在皮肤炎症中的作用。

This proposal is in response to a request for application (RFA) from the NIH to study chronic wounds. Chronic wounds are observed in millions of Americans with abnormalities of their sensory nervous system due to diabetes mellitus, spinal cord injury, peripheral vascular disease, and aging. We propose the novel concept that the frequency of chronic wounds in this population is not merely related to undetected trauma in denervated skin, but rather a reduction or absence of neuropeptides which are essential for normal tissue repair. Tissue repair is known to be abnormal in these populations resulting in morbidity, mortality, time loss from work, countless days of hospitalization or institutionalization and millions of dollars in health care costs. In this application we will test the hypotheses that: (1) An intact sensory nervous system is essential for normal cutaneous wound healing (2) chronic-wound development in neurologically impaired patients are the result of defects in acute wound healing, (3) neurologically impaired skin is characterized by abnormalities in the expression of substance P (SP), receptor (SPR), neutral endopeptidase (NEP), nerve growth factor (NGF) and/or NGF receptor (NGFR), and (4) deficits in skin integrity and wound healing can be overcome by therapeutic replacement or modulation of components of a defective cutaneous sensory nervous system. These hypotheses will be tested by the following Specific Aims: Specific Aim #1: To examine the expression and regulation of cutaneous SP, SPR, and NEP in the skin of normal and neurologically compromised patients; Specific Aim #2: To examine the expression and regulation of cutaneous NGF and NGFR in the skin of normal and neurologically compromised patients; Specific Aim #3: To examine the role of the neurological system in skin integrity and wound healing in neurologically impaired murine models and; Specific Aim #4 to determine if skin integrity and wound healing in neurologically impaired animals can be augmented by the modulation of cutaneous neurological system. These peptides will be localized in the skin by in situ hybridization and/or immunohistochemistry and quantitated by RNAse protection assay, Northern blot, RIA, ELISA, and/or bioassay. Our proposed studies may lead to novel therapeutic approaches for the treatment of poor skin integrity and chronic wounds in patients with diabetes and/or neurologic deficits and skin-prosthetic interactions. The research will be carried out by three groups of investigators who have ongoing collaborations. The San Francisco group provides expertise in neuropeptides with well characterized reagents. The Seattle group provides wound healing expertise with a well characterized human wound tissue library and access to patients with chronic non-healing ulcers and the Portland group provides expertise in cutaneous inflammation including the role of neuropeptides in cutaneous inflammation.