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.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY018343-05
Application #
8132912
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Mckie, George Ann
Project Start
2007-09-21
Project End
2013-08-31
Budget Start
2011-09-01
Budget End
2013-08-31
Support Year
5
Fiscal Year
2011
Total Cost
$334,320
Indirect Cost
Name
La Biomed Research Institute/ Harbor UCLA Medical Center
Department
Type
DUNS #
069926962
City
Torrance
State
CA
Country
United States
Zip Code
90502
Tsui, Shanli; Gao, Jie; Wang, Charles et al. (2012) CTCF mediates effect of insulin on glucagon expression. Exp Cell Res 318:887-95
Wang, Ling; Payton, Reid; Dai, Wei et al. (2011) Hyperosmotic stress-induced ATF-2 activation through Polo-like kinase 3 in human corneal epithelial cells. J Biol Chem 286:1951-8
Wang, Ling; Dai, Wei; Lu, Luo (2011) Hyperosmotic stress-induced corneal epithelial cell death through activation of Polo-like kinase 3 and c-Jun. Invest Ophthalmol Vis Sci 52:3200-6
Lu, Jiawei; Wang, Ling; Dai, Wei et al. (2010) Effect of hypoxic stress-activated Polo-like kinase 3 on corneal epithelial wound healing. Invest Ophthalmol Vis Sci 51:5034-40
Xu, Dazhong; Yao, Yixin; Jiang, Xuejun et al. (2010) Regulation of PTEN stability and activity by Plk3. J Biol Chem 285:39935-42
Xu, Dazhong; Yao, Yixin; Lu, Luo et al. (2010) Plk3 functions as an essential component of the hypoxia regulatory pathway by direct phosphorylation of HIF-1alpha. J Biol Chem 285:38944-50
Zheng, Wei; Zhao, Xiaoping; Wang, Jie et al. (2010) Retinal vascular leakage occurring in GABA Rho-1 subunit deficient mice. Exp Eye Res 90:634-40
Li, Tie; Lu, Luo (2007) Functional role of CCCTC binding factor (CTCF) in stress-induced apoptosis. Exp Cell Res 313:3057-65