ROLE OF THE NEUROLOGIC SYSTEM IN WOUND HEALING

这一建议是为了回应申请（RFA）的要求， 研究慢性创伤。在数百万人中观察到慢性伤口， 感觉神经系统异常的美国人， 糖尿病、脊髓损伤、外周血管疾病，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，而是减少或缺乏神经肽， 对正常组织的修复至关重要已知组织修复是 这些人群中的异常导致发病率、死亡率、时间损失 从工作，无数天的住院或机构， 数百万美元的医疗费用。在这个应用程序中，我们将测试 假设：（1）完整的感觉神经系统是必不可少的， 正常皮肤伤口愈合（2）慢性伤口发展， 神经功能受损的患者是急性创伤缺陷的结果， 愈合，（3）神经受损的皮肤的特征在于： P物质（SP）、受体（SPR） 中性内肽酶（NEP）、神经生长因子（NGF）和/或NGF受体 （NGFR），和（4）皮肤完整性和伤口愈合的缺陷， 通过治疗性替换或调节 皮肤感觉神经系统缺陷。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在皮肤中的表达和调节 正常和神经功能受损患者;具体目标#2： 检测皮肤中NGF和NGFR的表达和调节， 正常和神经受损患者的皮肤;具体目标#3： 检查神经系统在皮肤完整性和伤口中的作用 在神经受损的鼠模型中的愈合;具体目标#4至 确定神经受损患者的皮肤完整性和伤口愈合 动物可以通过调节皮肤神经系统来增强 系统这些肽将被定位在皮肤中的原位 杂交和/或免疫组织化学并通过RNA酶定量 保护测定、北方印迹、RIA、ELISA和/或生物测定。我们提出的 研究可能会导致新的治疗方法，用于治疗穷人 糖尿病患者的皮肤完整性和慢性伤口和/或 神经缺陷和皮肤-假体相互作用。这项研究将 由三组调查人员进行， 合作。旧金山弗朗西斯科集团提供专业知识， 神经肽与充分表征的试剂。西雅图集团提供 具有良好表征的人体伤口组织的伤口愈合专业知识 图书馆和访问慢性不愈合溃疡患者和 波特兰集团提供皮肤炎症方面的专业知识，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.