The Role of Epidermal Growth Factor in Sepsis

描述（由申请人提供）：脓毒症是危重患者死亡的主要原因，在美国每年有多达75万人患上这种疾病。肠道在脓毒症的发展中起着核心作用，被认为是全身炎症反应的“马达”。表皮生长因子（EGF）是一种肽，在几种损伤模型中显示出对肠上皮的保护作用。EGF主要参与调节各种细胞类型的细胞存活、细胞复制和细胞运动。目前尚不清楚EGF的保护作用是否仅针对肠道，或者EGF是否影响间接保护肠道的其他组织和器官系统。该建议的中心假设是外源性EGF通过直接调节肠上皮的完整性来提高脓毒症患者的生存率。由于EGF在脓毒症中的作用尚不清楚，本研究的第一个目的是确定EGF及其受体EGF- r如何调节两种脓毒症小鼠的肠道完整性：盲肠结扎和穿刺和肺炎。肠上皮细胞凋亡将通过以下方法进行评估：a)全身给予EGF， b)使用在其肠道中过度表达EGF的转基因小鼠，c)使用具有EGF- r信号传导能力缺陷的小鼠。上皮改变的功能意义将通过确定系统性表皮生长因子是否能改善生存，以及表皮生长因子的肠道特异性作用是否足以改善死亡率来检验。第二个目的是研究EGF预防脓毒症诱导的肠上皮细胞凋亡的机制。通过以肠道特异性方式靶向信号分子，我们将从机制上评估EGF的抗凋亡作用是否1)通过PI3K/Akt信号介导，2)依赖于NFkB激活。这些研究将有助于确定全身给药EGF在脓毒症中的功能意义及其作用机制。这对公共卫生有很大的影响，因为它可能被用作治疗一种每年导致21万患者死亡的疾病的新疗法。

DESCRIPTION (provided by applicant): Sepsis is a leading cause of death in critically ill patients, with up to 750,000 people developing this disease each year in the United States. The intestine plays a central role in the development of sepsis, and is considered to be the "motor" of the systemic inflammatory response. Epidermal growth factor (EGF) is a peptide that has been shown to protect the intestinal epithelium in several injury models. EGF is primarily involved in regulating cell survival, cell replication, and cell movement in various cell types. It is not clear if the protective effects of EGF are specific to the intestine, or if EGF influences other tissues and organ systems that indirectly protect the intestine. The central hypothesis of this proposal is that exogenous administration of EGF will improve survival in sepsis by directly modulating the integrity of the intestinal epithelium. Since the role of EGF in sepsis is unknown, the first aim of this investigation is to determine how EGF and its receptor, EGF-R, modulate intestinal integrity in mice subjected to two models of sepsis: cecal ligation and puncture and pneumonia. Intestinal epithelial apoptosis will be evaluated following manipulation of the EGF/EGF-R axis by a) systemic administration of EGF, b) using transgenic mice that over express EGF in their intestines and c) using mice with defective EGF-R signaling capacity. The functional significance of the epithelial alterations will be examined by determining if systemic EGF improves survival and if the intestine specific effects of EGF are sufficient to improve mortality. The second aim will then examine the mechanisms by which EGF prevents sepsis-induced intestinal epithelial apoptosis. By targeting signaling molecules in an intestine-specific fashion, we will mechanistically evaluate whether the anti-apoptotic effects of EGF are 1) mediated via PI3K/Akt signaling and 2) dependent on NFkB activation. These studies will help determine the functional significance of systemic administration of EGF in sepsis and the mechanisms underlying its effects. This has large public health implications as it could potentially be used as a novel therapeutic in the treatment of a disease that kills 210,000 patients a year.