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

• 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
• 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

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是重要的，该功能保护角膜、透镜和其他下方的眼部结构免受环境损害引起的损伤。紫外线（UV）照射和其他生物危害物可诱导应激相关的细胞反应，导致损伤伤口愈合的动态过程。我们实验室新获得的数据表明，紫外线应激诱导的细胞信号传导反应导致角膜上皮细胞在细胞最终凋亡之前的早期阶段的伤口愈合延迟。初步数据表明：1）UV应激诱导的细胞反应由膜中K+通道的超活化开始; 2）细胞内K+离子的快速损失导致细胞体积收缩;和3）细胞收缩诱导JNK信号传导途径中支架酪氨酸激酶（FAK/Src）和MEKK 1/4的活化。随后，JNK级联的激活又增加了p53的磷酸化水平，导致细胞周期停滞。在角膜上皮中，FAK很可能将来自UV诱导的体积收缩的输入的信号协调到JNK信号传导途径。基于初步的研究结果，我们假设，紫外线应力诱导的角膜上皮伤口愈合迟缓是由复杂的串扰信号转导过程，涉及改变细胞体积，增加支架酪氨酸激酶活性，激活JNK级联和细胞周期停止。将进行并研究三个具体目标以检验该假设：1）支架酪氨酸激酶活化和细胞骨架重组，2）JNK信号传导途径中FAK/Src和MEKK 1/4的活化之间的串扰，和3）信号传导组分对UV诱导的伤口愈合延迟的影响。我们预测支架蛋白激酶在紫外线诱导的细胞收缩和JNK级联激活的联系中起重要作用，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，UV应激诱导的JNK级联的激活和随后发生的ONA片段化是触发角膜上皮细胞凋亡的原因。因此，UV应激诱导的信号传导事件的研究提供了重要的见解，了解的机制，角膜上皮伤口愈合过程中的损害所造成的环境侮辱。