ROLE OF THE NEUROLOGIC SYSTEM IN CUTANEOUS ANGIOGENESIS

描述：(改编自申请人的摘要)-这是一份重新提交的文件 竞争性地更新以前的提案，该提案审查了 皮肤伤口愈合中的神经系统。在之前的资助期间 期间，有证据表明，皮肤感觉神经系统和 释放的神经肽能够调节许多重要的 皮肤中炎症和伤口愈合反应的成分。这 应用程序将检验感觉神经系统是 能够调节皮肤血管生成的许多基本方面 通过P物质、降钙素基因等神经肽的释放 相关肽(CGRP)。释放的神经肽激活特定的皮肤 微血管内皮细胞(DMEC)神经肽受体促进 血管生成。这种相互作用可能在调节正常和 皮肤中的病理过程。本申请的具体目标是： 1)测定特定感觉神经肽对DMEC的调节能力 直接血管生成反应；2)测定激活的轴突的容量 直接调控DMEC的血管生成反应；3)测定 调节皮肤血管生成的皮肤神经系统；以及4) 确定皮肤神经系统调节的能力 皮肤伤口愈合中的血管生成。特定神经肽的作用 以及它们各自在调节血管生成中的受体将在 利用小鼠和人体模型系统进行体外和体内实验。离体 将通过测量微血管来评估DMEC的血管生成反应 内皮细胞(A)增殖，(B)趋化/趋化运动，(C)基质 金属蛋白酶/基质金属蛋白酶的组织抑制因子，(D)内皮细胞 细胞源性血管生成因子的产生和(E)内皮管 形成/萌发。激活的感觉神经元与细胞共培养的能力 将测定DMEC诱导血管生成活性。活体皮肤 正常成人局部注射神经肽后对辣椒素的血管新生反应 在伤口愈合期间，将通过直接血管计数和 免疫组织化学染色后计算机辅助图像分析。这些研究将 进一步认识神经系统在血管生成中的作用 并可能为广泛的皮肤过程带来新的疗法 包括炎症、伤口愈合和肿瘤。

DESCRIPTION: (Adapted from the applicant's abstract) - This is a resubmission of a competitive renewal of a previous proposal that examined the role of the neurological system in cutaneous wound healing. During the previous funding period, it was demonstrated that the cutaneous sensory neurological system and released neuropeptides were capable of modulating a number of important components of inflammation and wound healing responses in the skin. This application will test the general hypothesis that the sensory nervous system is capable of regulating a number of essential aspects of cutaneous angiogenesis by the release of neuropeptides such as substance P (SP) and calcitonin gene related peptide (CGRP). The released neuropeptides activate specific dermal microvascular endothelial cell (DMEC) neuropeptide receptors to promote angiogenesis. This interaction might play a key role in modulating normal and pathological processes in the skin. The specific aims of this application are: 1) Determine the capacity of specific sensory neuropeptides to modulate DMEC angiogenic responses directly; 2) determine the capacity of activated neurites to modulate DMEC angiogenic responses directly; 3) determine the capacity of the cutaneous neurological system to modulate angiogenesis in the skin; and 4) determine the capacity of the cutaneous neurological system to modulate angiogenesis in wound healing of the skin. The role of specific neuropeptides and their respective receptors in modulating angiogenesis will be determined in vitro and in vivo utilizing both murine and human model systems. In vitro DMEC angiogenesis responses will be assessed by measuring microvascular endothelial cell (a) proliferation, (b) chemotaxis/ chemokinesis, (c) matrix metalloproteinase (MMP)/tissue inhibitor of MMP production, (d) endothelial cell derived angiogenic factor production, and (e) endothelial tube formation/sprouting. The ability of activated sensory neurons co-cultured with DMEC to induce angiogenic activities will be determined. In vivo cutaneous angiogenic responses to topical capsaicin, injected neuropeptides, in normal and during wound healing will be measured by direct vessel counts and computer-assisted image analysis after immunostaining. These studies will further basic understanding of the role of the nervous system in angiogenesis and could lead to novel therapies for a wide range of cutaneous processes including inflammation, wound healing, and neoplasia.