Mechanisms of Environmental Stress Affecting Corneal Epithelial Wound Healing

环境应激影响角膜上皮伤口愈合的机制

基本信息

批准号：
7298563
负责人：
LUO LU
金额：
$ 34.04万
依托单位：
LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-21 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7298563
关键词：
4-Aminopyridine Abbreviations Affect Apoptosis Biohazardous Substance Cell Cycle Cell Cycle Arrest Cell Cycle Progression Cell Cycle Regulation Cell Volumes Cells Cessation of life Commit Complex Cornea Cytoskeleton Data Dose Epidermal Growth Factor Epithelial Cells Event Exposure to Focal Adhesion Kinase 1 Hyperactive behavior Ions KRP protein Link MAP3K1 gene Mediating Membrane Mitogen-Activated Protein Kinase Kinases Mus Oryctolagus cuniculus Pathway interactions Phosphorylation Phosphotransferases Platelet-Derived Growth Factor Play Potassium Channel Process Protein Kinase Protein Tyrosine Kinase Rate Research Personnel Role Scaffolding Protein Signal Pathway Signal Transduction Staging Stress Structure TP53 gene Testing Time Tumor Necrosis Factor-alpha Tumor Necrosis Factors Voltage-Gated Potassium Channel Wound Healing base computerized data processing corneal epithelium human TNF protein insight lens prevent programs response scaffold src-Family Kinases stress-activated protein kinase 1 ultraviolet ultraviolet irradiation

项目摘要

DESCRIPTION (provided by applicant): The dynamic process of wound healing is important for maintaining the corneal epithelial layer's normal function that protects the cornea, lens and other underlying ocular structures from damage caused by environmental insults. Ultraviolet (UV) irradiation and other biohazards can induce stress-related cellular responses resulting in damage to the dynamic process of wound healing. Newly obtained data from our lab suggest that that UV stress-induced cellular signaling responses resulting in wound healing retardation in corneal epithelial cells during the early stage before the cells eventually commit apoptosis. Preliminary data suggest that: 1) UV stress-induced cellular response is started by hyperactivation of K+ channels in the membrane; 2) the fast loss of intracellular K+ ions causes cell volume shrinkage; and 3) cell shrinkages induce activations of scaffolding tyrosine kinases (FAK/Src) and MEKK1/4 in the JNK signaling pathway. Subsequently, the activation of JNK cascades in turn increases the phosphorylation level of p53 leading to cell cycle arrest. It is very likely in the corneal epithelium that FAK coordinates signals from inputs of UV-induced volume shrinkage to the JNK signaling pathway. Based on the preliminary study results, we hypothesize that UV stress-induced corneal epithelial wound healing retardation is regulated by complex crosstalks in signaling processes involving altered cell volume, increased scaffolding tyrosine kinase activity, activated JNK cascades and cell cycle cessation. Three specific aims will be performed and studied to test this hypothesis: 1) scaffolding tyrosine kinase activation and cytoskeleton reorganization, 2) crosstalk among activations of FAK/Src and MEKK1/4 in the JNK signaling pathway, and 3) effects of signaling components on UV- induced wound healing retardation. We predict that scaffolding protein kinases play important roles in the linkage of UV-induced cell shrinkage and the activation of JNK cascades, resulting in a quick inhibition of cell cycle progression that causes corneal epithelial wound healing retardation. However, UV stress-induced activation of JNK cascades and ONA fragmentation that occurs in a later time are responsible for triggering apoptosis in corneal epithelial cells. Thus, studies of UV stress-induced signaling events provide significant insight for understanding the mechanisms that underlie the corneal epithelial wound healing processes from damages caused by environmental insults.

描述（由申请人提供）：伤口愈合的动态过程对于维持角膜上皮层的正常功能很重要，该功能可保护角膜，镜头和其他潜在的眼结构免受环境损害造成的损害。紫外线（UV）辐射和其他生物危害可以诱导与压力相关的细胞反应，从而损害伤口愈合的动态过程。从我们的实验室中获得的新数据表明，在细胞最终造成细胞凋亡之前的早期阶段，紫外应力诱导的细胞信号反应导致角膜上皮细胞的伤口愈合。初步数据表明：1）紫外应力诱导的细胞反应是由膜中K+通道的过度激活开始的； 2）细胞内K+离子的快速损失导致细胞体积收缩； 3）细胞收缩诱导JNK信号通路中的脚手架酪氨酸激酶（FAK/SRC）和MEKK1/4的激活。随后，JNK级联反弹的激活又增加了p53的磷酸化水平，从而导致细胞周期停滞。在角膜上皮中很可能会从紫外线诱导的体积收缩输入到JNK信号通路的输入中coordins坐标。基于初步研究结果，我们假设紫外线胁迫诱导的角膜上皮伤口愈合迟缓受到复杂的串扰，在涉及细胞体积变化的信号过程中，脚手架酪氨酸激酶活性增加，激活JNK级联反应和细胞周期静止。将进行三个具体目的并研究以检验以下假设：1）脚手架酪氨酸激酶激活和细胞骨架重组，2）在JNK信号途径中FAK/SRC和MEKK1/4激活之间的串扰，以及3）信号组件对UV施加的效果对UV施加的伤口受伤后的可治愈后的效果。我们预测，脚手架蛋白激酶在紫外线诱导的细胞收缩和JNK级联反应的激活中起着重要作用，从而快速抑制细胞周期进程，从而导致角膜上皮伤口愈合。然而，紫外应力诱导的JNK级联反应和以后发生的ONA碎片化是为了触发角膜上皮细胞的凋亡。因此，对紫外应力诱导的信号事件的研究为理解角膜上皮伤口愈合过程的机制提供了重要的见解，这些机制是由于环境损害引起的损害。