Surgical Wound Repair: Role of A Neuroendothelial Axis

手术伤口修复：神经内皮轴的作用

基本信息

批准号：
7742370
负责人：
NICOLE SIMONE GIBRAN
金额：
$ 9.86万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-09-01 至 2009-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7742370
关键词：
Actins Address Affect Applications Grants Area Blood Vessels Blood capillaries Burn injury Burning Pain Cell Adhesion Molecules Cell Proliferation Cell Shape Cell surface Cells Cicatrix Clinical Complex Coupled Cutaneous Cytoskeleton Data Deformity Development Diabetes Mellitus Diabetic mouse Endothelial Cells Epithelial Esthesia Evaluation Focal Adhesions GTP-Binding Proteins Genetic Transcription Goals Growth Growth Factor Healed Hypertrophic Cicatrix IL8 gene Impaired wound healing In Vitro Inflammation Inflammation Mediators Inflammatory Response Injury Integrins Interleukin-8 Kinetics Limb structure Mediating Mediator of activation protein Modeling Mus Mutant Strains Mice Natural regeneration Nerve Nerve Fibers Nerve Growth Factors Nerve Regeneration Neurons Neuropeptides Nitric Oxide Nitric Oxide Synthase Nitric Oxide Synthase Type I PC12 Cells Pain Pathway interactions Patients Process Production Pruritus Regulation Relaxation Research Personnel Role Signal Pathway Signal Transduction Skin Substance P Surgical wound Testing Transgenic Mice Ulcer United States Vascular Endothelial Growth Factors Wound Healing afferent nerve angiogenesis capillary cutaneous sensory nerve disability healing human NOS2A protein human NOS3 protein in vitro Model mutant nerve supply neuroinflammation neurotrophic factor programs receptor response response to injury wound

项目摘要

DESCRIPTION (provided by applicant): This proposal explores cell signaling pathways that occur between cutaneous sensory nerve fibers and endothelial cells during response to cutaneous injury. With increased patient survival following large burn injuries, disability due to hypertrophic scar formation has become an important clinical problem that affects as many as 100,000 patients per year in the United States. This abnormal response to injury results in significant patient misery due to both the unsightly deformity and also devastating itching and pain. The scars have hypervascularity and increased innervation. In contrast, non-healing ulcers of diabetes mellitus have microangiopathy and decreased innervation. We anticipate that in hypertrophic scars increased endothelial cell proliferation and neurotrophin synthesis leads to the hypervascularity and pruritis. Our Iong term hypothesis is that followinq cutaneous injury, 1) sensory nerve fibers secrete neuropeptides such as substance P that regulate endothelial cell response to injury and 2) microvascular endothelial cells secrete neurotrophins that regulate nerve fiber regeneration. We will test our hypothesis by addressing the following aims: Aim 1: To determine intracellular mechanisms by which substance P regulates endothelial cell proinflammatory response. We will determine whether the substance P induces endothelial cell production of nerve growth factor, vascular endothelial growth factor and interleukin 8 by 1) G-protein coupled pathways or 2) cell shape change and cytoskeleton reorganization. Aim 2: To determine the role of nitric oxide synthase in substance P mediated response to injury by endothelial cells. We will determine whether substance P signaling pathways leading to nerve growth factor, vascular endothelial growth factor and interleukin 8 synthesis depend on nitric oxide. Aim 3: To determine which endothelial cell derived mediators regulate nerve cell sprouting. We will evaluate the second limb of our hypothesis by identifying endothelial cell-derived neurotrophins that regulate sensory nerve fiber sprouting. Using an in vitro model of nerve growth, we will verify that the manipulations in aims 1 and 2 diminish soluble mediators that are responsible for nerve differentiation. Aim 4: To determine how neuropeptide activity in transgenic mice and mutant diabetic mice alters response to injury. We will determine how substance P modulates cutaneous response to injury using an excisional wound model in normal mice, in diabetic mice and in mice with targeted disruption of neuronal nitric oxide synthase, inducible nitric oxide synthase or endothelial nitric oxide synthase.

描述（由申请人提供）：该提案探讨了对皮肤损伤的反应期间皮肤感觉神经纤维和内皮细胞之间发生的细胞信号传导途径。随着烧伤大伤后的患者生存率增加，由于肥厚性疤痕形成而导致的残疾已成为一个重要的临床问题，在美国，每年影响多达100,000名患者。这种对损伤的异常反应导致患者的严重痛苦，这既是难看的畸形，又破坏了瘙痒和疼痛。疤痕具有高血管性和神经支配的增加。相反，糖尿病的非愈合溃疡具有微血管病和神经支配的减少。我们预计，在肥大性疤痕中会增加内皮细胞增殖，而神经营养蛋白合成会导致高血管和瘙痒。我们的离子术语假设是，跟随皮肤损伤，1）感觉神经纤维分泌神经肽，例如调节内皮细胞对损伤的反应的物质P和2）微血管内皮细胞分泌神经营养蛋白，这些神经植物会调节神经纤维再生。我们将通过解决以下目的来检验我们的假设：目标1：确定物质调节内皮细胞促炎反应的细胞内机制。我们将确定该物质P是否诱导神经生长因子的内皮细胞产生，血管内皮生长因子和白介素8 by 1）G蛋白偶联途径还是2）细胞形状变化和细胞骨架重组。目标2：确定一氧化氮合酶在物质p介导的内皮细胞介导的反应中的作用。我们将确定导致神经生长因子，血管内皮生长因子和白介素8合成的物质P信号传导途径是否取决于一氧化氮。目标3：确定哪种内皮细胞衍生的介体调节神经细胞的发芽。我们将通过识别调节感觉神经纤维发芽的内皮细胞衍生的神经营养蛋白来评估假设的第二肢。使用神经生长的体外模型，我们将验证目标1和2中的操作是否减少了负责神经分化的可溶性介体。目标4：确定转基因小鼠和突变糖尿病小鼠的神经肽活性如何改变对损伤的反应。我们将在正常小鼠，糖尿病小鼠和具有靶向破坏神经元一氧化氮合酶，可诱导的一氧化氮合酶或内皮一氧化氮合酶的小鼠中，在正常小鼠，糖尿病小鼠和小鼠中，使用p造成伤口模型来确定物质如何调节对损伤的皮肤反应。