Molecular Regulation of Corneal Wound Healing

角膜伤口愈合的分子调控

基本信息

批准号：
7995179
负责人：
Fu-Shin X Yu
金额：
$ 36.12万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1995
资助国家：
美国
起止时间：
1995-08-01 至 2013-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7995179
关键词：
1-Phosphatidylinositol 3-Kinase AKT Signaling Pathway Abbreviations Acetylcysteine Adverse effects Affect Animal Model Antioxidants Attenuated Biological Preservation Blindness Clinical Cornea Corneal Injury Defect Diabetes Mellitus Diet Disease Epidermal Growth Factor Receptor Epithelial Epithelial Cells Epithelium Extracellular Signal Regulated Kinases Family suidae Generations Glucose Goals Grant Healed Health Homeostasis Human Hyperglycemia Impaired wound healing Insulin-Dependent Diabetes Mellitus Keratitis Keratopathy Knowledge Laboratories Lead Ligands Light Literature Measures Mediating Mediator of activation protein Modeling Molecular Molecular and Cellular Biology Organ Culture Techniques Oxidative Stress Pathogenesis Pathway interactions Patients Play Property Proto-Oncogene Proteins c-akt Publishing Rattus Reactive Oxygen Species Receptor Activation Receptor Protein-Tyrosine Kinases Receptor Signaling Recurrence Regulation Role Serum Signal Pathway Signal Transduction Streptozocin Testing Vision Vitrectomy Wound Healing base cell injury corneal epithelium diabetic diabetic patient diabetic rat effective therapy extracellular healing heparin-binding EGF-like growth factor microbial normal aging novel oxidative damage patient population receptor downregulation response restoration therapeutic development therapy development wound

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of the laboratory has been to obtain basic information about the molecular and cellular biology of corneal wound healing. The studies in the current grant period demonstrated that epidermal growth factor receptor (EGFR) is the key receptor tyrosine kinase activated upon wounding, and the wound-induced activation of EGFR and its downstream signaling pathways, particularly ERK and PI3K, play a central role in mediating corneal epithelial wound healing. While in normal cornea an epithelial wound is usually healed in a timely fashion without any complications, epithelial wound healing is considerably delayed in the corneas of diabetic patients. The delayed healing of the epithelial defect (termed diabetic keratopathy) may result in sight threatening complications, such as persistent epithelial defect, recurrent erosion, and microbial keratitis. Preliminary studies using streptozotocin (SZT)-treated rats as a type 1 diabetes model and human diseased corneas revealed that EGFR signaling, in particular PI3K pathways, is compromised in the epithelia of diabetic rat corneas and of human diabetic, but not in normal and diet-controlled corneas. Our published and preliminary studies lead to the hypothesis that the tightly regulated EGFR signaling is abrogated by hyperglycemia in the epithelium and that strengthening of the weakened EGFR signaling, along with reducing oxidative stress, may preserve epithelial integrity and promote epithelial wound healing in the diabetic corneas. Three specific aims are proposed to test this hypothesis. 1) To characterize EGFR signaling pathways and oxidative damage in SZT diabetic rat corneas. Alterations of EGFR signaling in the epithelia of SZT-induced and human diabetic corneas will be characterized and correlated to the epithelial abnormalities observed in these diseased corneas. 2) To determine how hyperglycemia affects EGFR signaling and epithelial integrity and function in the cornea. Cultured porcine corneas and primary human corneal epithelial cells will be used. The effects of high glucose that mimics hyperglycemia on the generation of reactive oxygen species, on EGFR signaling, and on epithelial integrity and function including barrier properties and wound healing will be assessed. 3) To determine how manipulation of EGFR-signaling pathways might be used to accelerate epithelial wound healing in diabetic corneas. EGFR ligands will be combined with antioxidant and their synergistic effects on promoting epithelial wound healing and barrier function will be elucidated. The results of these proposed studies should shed light on the mechanisms underlying pathogenesis of diabetic keratopathy and lead to the identification of effective treatments for the delayed diabetic corneal epithelial wound healing which currently are lacking. PUBLIC HEALTH RELEVANCE This study will use animal models of diabetes, a unique ex vivo corneal organ culture model, cultured human corneal epithelial cells, and human diabetic corneas to study the mechanisms underlying pathogenesis of diabetic keratopathy, a disease with severe abnormalities in two thirds of patients. In the light of an ever-increasing patient population with diabetes and the lack of effective treatments for the disease, this study is of paramount importance and may lead to the development of therapeutics for treating the disease and for promoting delayed epithelial wound healing often associated with diabetic vitrectomy.

描述（由申请人提供）：实验室的长期目标是获得有关角膜伤口愈合的分子和细胞生物学的基本信息。当前赠款期间的研究表明，表皮生长因子受体（EGFR）是受伤后激活的关键受体酪氨酸激酶，伤口引起的EGFR及其下游信号传导途径的激活，尤其是ERK和PI3K，尤其是ERK和PI3K，在介导角膜上皮上皮上皮上皮上皮上的核心作用。尽管在正常的角膜中，通常会及时愈合上皮伤口而没有任何并发症，但糖尿病患者角膜的上皮伤口愈合会大大延迟。上皮缺陷（称为糖尿病性角膜病）的延迟治愈可能导致视力威胁并发症，例如持续的上皮缺陷，复发性侵蚀和微生物角膜炎。使用链霉菌素（SZT）处理的大鼠作为1型糖尿病模型和人类疾病角膜的初步研究表明，在糖尿病大鼠的上皮中，EGFR信号传导，尤其是PI3K途径在人类糖尿病和人类糖尿病的上皮中受到损害，但在正常和日托控制的角膜中。我们发表的初步研究导致了以下假设：上皮细胞中高血糖的严格调节的EGFR信号传导消除了，并且增强EGFR信号传导的增强以及减少氧化应激，以及减少的氧化应激，可以保留上皮完整性并促进糖尿病性角膜中上皮伤口愈合。提出了三个特定目标来检验这一假设。 1）表征EGFR信号通路和SZT糖尿病大鼠角膜中的氧化损伤。 SZT诱导和人类糖尿病角膜上皮中EGFR信号传导的改变将与这些患病角膜中观察到的上皮异常相关。 2）确定高血糖如何影响角膜中的EGFR信号传导和上皮完整性和功能。将使用培养的猪角膜和原发性角膜上皮细胞。高葡萄糖模仿高血糖对活性氧，EGFR信号传导以及上皮完整性和功能（包括屏障特性和伤口愈合）的影响。 3）确定如何使用EGFR信号途径的操纵来加速糖尿病角膜上的上皮伤口愈合。 EGFR配体将与抗氧化剂结合使用，它们对促进上皮伤口愈合和屏障功能的协同作用将得到阐明。这些提出的研究的结果应阐明糖尿病角膜病的发病机理的基础机制，并导致鉴定出目前缺乏的延迟糖尿病角膜上皮伤口愈合的有效治疗方法。公共卫生相关性这项研究将使用糖尿病的动物模型，一种独特的离体角膜器官培养模型，培养的人角膜上皮细胞和人类糖尿病角膜来研究糖尿病性角质病的发病机理，这是三分之二的患者中有严重异常的疾病。鉴于糖尿病患者不断增加的患者人群，缺乏对疾病的有效治疗，这项研究至关重要，可能导致治疗疾病的治疗和促进延迟的上皮伤口愈合通常与糖尿病胸腔切除术有关。