The long-term goal of the laboratory has been to obtain basic information about the molecular and cellular biology of corneal wound healing. During the current grant period, it was discovered that the two cellular components that specialize in sensing environmental changes, namely sensory neurons and antigen presenting dendritic cells (DCs), are functionally interdependent within the platform of corneal epithelium. Hyperglycemia drastically reduced corneal sensitivity and the density of sensory nerve fibers and endings in uninjured corneas, and significantly impaired re-innervation in post-wounding corneas. DCs, on the other hand, were found to co-localize with the nerve fiber innervating the epithelium and to ultimately contact with the nerve endings of the subbasal nerve plexus. Furthermore, in healing corneal epithelia, the number of DC cells was much reduced and the interconnections of DC with innervating nerve fibers/endings were disrupted in DM corneas, suggesting that DCs in these corneas have lost their ability to protect sensory nerves and to guide neuron regeneration post-wounding due to hyperglycemia. In addition to the DC-released neurotrophic factors, the wound-induced epithelium expression of nerve growth factor (NGF) was suppressed in DM CECs. Our published and preliminary studies led to the hypothesis that the altered interactions of CECs and DCs with sensory nerves result in diabetic neurotrophic keratopathy (DNK) and in delayed epithelial wound healing in diabetic corneas.
The specific aims are: 1. To unravel the molecular characterization of DNK and its adverse effects on corneal epithelial integrity and intraepithelial dendritic cell function. This can be tested by measuring the relative density of sensory nerves and the contents of neuropeptides, and their correlation to epithelial signal transduction and to barrier function and to DC activation in NL versus DM corneas. 2. To determine the mechanisms by which dendritic cells guide epithelial innervation and post-wounding regeneration in NL corneas and their contributions to diabetic peripheral neuropathy (DPN). This can be tested by assessing the defects of DCs and CNTF and/or NT3 contents in diabetic corneas, and by delineating the functional requirements for sensory nerve innervation and regeneration in vivo and neurite growth in vitro in trigeminal neuron-DC co-culture. 3. To decipher how hyperglycemia disrupts epithelium-sensory nerve communication and causes delayed wound healing in the cornea. This can be tested by the epithelium-targeted expression of NGF, the blocking of NGF signaling in sensory innervation and regeneration in vivo, and neuron growth in vitro in trigeminal neuron-CEC-DC co-culture. The results from this proposal should increase our understanding of diabetic neurotrophic keratopathy and of delayed epithelial wound healing at the molecular and cellular levels, and should lead to the development of therapies that control diabetic neurotrophic keratopathy where there is an unmet clinical need.

Public Health Relevance

This proposal is to determine the mechanisms underlying the pathogenesis of neurotrophic keratopathy and delayed epithelial wound healing in diabetic corneas. The knowledge gained will be critical for the long-term goal of developing mechanism-based, efficacious therapeutic modalities for treating diabetic neurotrophic keratopathy/diabetic peripheral neuropathy and delayed wound healing.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Diseases and Pathophysiology of the Visual System Study Section (DPVS)
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Mckie, George Ann
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Wayne State University
Schools of Medicine
United States
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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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