Role of Signal Transduction in Burn and Wound Healing

严重损伤的患者不是一个同质的群体，他们的炎症反应状态是不断变化的，从过度活化到免疫抑制。调节这些反应的细胞控制开关包括广泛的细胞内信号转导途径网络，如丝裂原活化蛋白激酶（MAPK）家族。我们集中在p38和ERK，两个重要的MAPK家族，调节炎症反应和细胞凋亡。为了阐明MAPK激活的不同途径，我们设计了一个体外实验模型。使用来自野生型、CD14敲除和脂多糖结合蛋白（LBP）敲除小鼠的腹腔巨噬细胞，我们将研究响应于脂多糖（LPS）刺激的细胞和MAPK激活的不同途径。令人惊讶的是，我们的初步数据表明，LPS激活p38 MAPK在CD14敲除一样多或超过野生型。这表明LPS诱导的p38 MAPK活化的非CD14途径。在第二组实验中，我们将通过改变MAPK活化来研究潜在的治疗方法。在工业化国家中，美国因烧伤而死亡和残疾的人数居首位。在最初的热损伤之后，存在持续至数天的进行性细胞死亡和凋亡。在上皮细胞中，p38活化是促凋亡的，而ERK活化抑制凋亡。我们假设抑制p38和/或激活ERK将抑制热损伤引起的细胞死亡。目的是防止部分皮层烧伤转化为全皮层烧伤，部分皮层烧伤可以初步愈合。在体内热损伤伤口模型中，我们将研究局部丝裂原活化蛋白激酶抑制剂/活化剂的有效性和安全性。我们将首先描述皮肤MAPK激活，细胞因子的产生，和上皮细胞凋亡在小鼠烧伤损伤的反应。然后，我们将使用p38和ERK激活剂的局部抑制剂来研究它们对细胞死亡的影响。这项赠款提案包括一项培训计划，通过完成核心课程和与导师和顾问经常举行的教学会议。候选人将在斯图尔特博士的指导下获得先进技术的知识。王先生在做研究计划的时候。我们的目标是让候选人成为一个独立的研究人员与他自己的赠款。

Critically injured patients are not a homogenous group, and the state of their inflammatory response is in flux, ranging from hyperactivation to immunosuppression. The cellular control switches that regulate these responses include an extensive network of intracellular signal transduction pathways, such as the mitogenactivatedprotein kinase (MAPK) families. We have focused on p38 and ERK, two important MAPK families, regulating inflammatory response and apoptosis. In order to elucidate the different pathways involved in MAPK activation we have devised an in vitro experimental model. Using peritoneal macrophages from wild type, CD14 knockout, and lipopolysaccharide-binding-protein (LBP) knockout mice, we will examine different pathways of cell and MAPK activation in response to lipopolysaccharide (LPS) stimulation. Surprisingly, our preliminary data demonstrated that LPS activates p38 MAPK in the CD14 knockouts as much or more than the wild type. This suggests a non-CD14 pathway for LPS-induced p38 MAPK activation. In a second set of experiments, we will investigate the potential therapeutic approaches by modifying MAPK activation. The United States ranks first among industrialized nations in death and disability from burn injuries. There is a progressive cell death and apoptosis that extends to several days after the initial thermal injury. In epithelial cells p38 activation is pro-apoptotic, while ERK activation inhibits apoptosis. We hypothesize that inhibiting p38 and/or activating ERK will inhibit cell death in response to thermal injury. The goal is to prevent conversion of a partial-thickness burn, which may heal primarily, to a full-thickness burn. In an in vivo thermal injury wound model, we will investigate the efficacy and safety of topical mitogen-activated protein kinase inhibitors/activators. We will first characterize the dermal MAPK activation, cytokine production, and epithelial apoptosis in response to burn injury in mice. We will then use topical inhibitors of both p38 and activators of ERK to study their effect on cell death. This grant proposal is composed of a training plan through the completion of core curriculum of courses and frequent didactic sessions with mentors and advisors. The candidate will gain knowledge of advanced techniques under the tutlelage of Dr. Stewart C. Wang, while working on the research proposal. The goal is for the candidate to become an independent researcher with his own grants.