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.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY010869-16
Application #
7995179
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Mckie, George Ann
Project Start
1995-08-01
Project End
2013-11-30
Budget Start
2010-12-01
Budget End
2011-11-30
Support Year
16
Fiscal Year
2011
Total Cost
$361,152
Indirect Cost
Name
Wayne State University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202
Gao, Nan; Liu, Xiaowei; Wu, Jiayin et al. (2017) CXCL10 suppression of hem- and lymph-angiogenesis in inflamed corneas through MMP13. Angiogenesis 20:505-518
Ross, Bing X; Gao, Nan; Cui, Xinhan et al. (2017) IL-24 Promotes Pseudomonas aeruginosa Keratitis in C57BL/6 Mouse Corneas. J Immunol 198:3536-3547
Dong, Chen; Gao, Nan; Ross, Bing X et al. (2017) ISG15 in Host Defense Against Candida albicans Infection in a Mouse Model of Fungal Keratitis. Invest Ophthalmol Vis Sci 58:2948-2958
Zhang, Xilin; Liu, Queping; Wang, Jie et al. (2016) TIM-4 is differentially expressed in the distinct subsets of dendritic cells in skin and skin-draining lymph nodes and controls skin Langerhans cell homeostasis. Oncotarget 7:37498-37512
Gao, Nan; Yan, Chenxi; Lee, Patrick et al. (2016) Dendritic cell dysfunction and diabetic sensory neuropathy in the cornea. J Clin Invest 126:1998-2011
Gao, Nan; Lee, Patrick; Yu, Fu-Shin (2016) Intraepithelial dendritic cells and sensory nerves are structurally associated and functional interdependent in the cornea. Sci Rep 6:36414
Dandekar, Aditya; Qiu, Yining; Kim, Hyunbae et al. (2016) Toll-like Receptor (TLR) Signaling Interacts with CREBH to Modulate High-density Lipoprotein (HDL) in Response to Bacterial Endotoxin. J Biol Chem 291:23149-23158
Zhang, X; Gu, J; Yu, F-S et al. (2016) TGF-?1-induced transcription factor networks in Langerhans cell development and maintenance. Allergy 71:758-64
Yan, Chenxi; Gao, Nan; Sun, Haijing et al. (2016) Targeting Imbalance between IL-1? and IL-1 Receptor Antagonist Ameliorates Delayed Epithelium Wound Healing in Diabetic Mouse Corneas. Am J Pathol 186:1466-80
Gao, Nan; Kumar, Ashok; Yu, Fu-Shin X (2015) Matrix Metalloproteinase-13 as a Target for Suppressing Corneal Ulceration Caused by Pseudomonas aeruginosa Infection. J Infect Dis 212:116-27

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