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：
7682149
负责人：
LUO LU
金额：
$ 34.59万
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/7682149
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 Research Personnel Role Scaffolding Protein Signal Pathway Signal Transduction Staging Stress Structure TP53 gene Testing Time Tumor Necrosis Factor-alpha Tumor Necrosis Factors UV induced Voltage-Gated Potassium Channel Wound Healing base computerized data processing corneal epithelium 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非常重要，从而保护角膜、晶状体和其他眼部结构免受环境侵害造成的损害。紫外线 (UV) 照射和其他生物危害会诱发与应激相关的细胞反应，从而损害伤口愈合的动态过程。我们实验室最新获得的数据表明，紫外线应激诱导的细胞信号反应导致角膜上皮细胞在细胞最终凋亡之前的早期伤口愈合延迟。初步数据表明：1）紫外线应激诱导的细胞反应是由膜中 K+ 通道的过度激活启动的； 2）细胞内K+离子快速丢失导致细胞体积缩小； 3) 细胞收缩诱导 JNK 信号通路中支架酪氨酸激酶 (FAK/Src) 和 MEKK1/4 的激活。随后，JNK 级联的激活反过来又增加了 p53 的磷酸化水平，导致细胞周期停滞。在角膜上皮中，FAK 很可能协调来自紫外线诱导的体积收缩输入到 JNK 信号通路的信号。根据初步研究结果，我们假设紫外线应激诱导的角膜上皮伤口愈合迟缓是由信号传导过程中复杂的串扰调节的，这些信号传导过程涉及细胞体积改变、支架酪氨酸激酶活性增加、JNK级联激活和细胞周期停止。将执行和研究三个具体目标来检验这一假设：1）支架酪氨酸激酶激活和细胞骨架重组，2）JNK 信号通路中 FAK/Src 和 MEKK1/4 激活之间的串扰，以及 3）信号成分对紫外线引起的伤口愈合迟缓。我们预测支架蛋白激酶在紫外线诱导的细胞收缩和 JNK 级联激活的联系中发挥重要作用，从而导致细胞周期进程的快速抑制，从而导致角膜上皮伤口愈合迟缓。然而，紫外线应激诱导的 JNK 级联激活和稍后发生的 ONA 碎片是触发角膜上皮细胞凋亡的原因。因此，对紫外线应激诱导的信号事件的研究为理解环境损伤造成的角膜上皮伤口愈合过程的机制提供了重要的见解。