The anterior surface of the eye functions as a barrier to the external environment and protects the delicate underlying structures from injury, in part, through the elaboration of the limbal and corneal epithelia. As self-renewing tissues, these epithelia are governed by stem cells, which play a crucial role in tissue homeostasis, regeneration, transplantation, gene therapy and in the pathogenesis of several anterior ocular surface diseases. Equally important for proper vision is the need for corneal transparency, which is achieved through avascularity. It is well-accepted that the limbal epithelium is the site f the corneal epithelial stem cells;however, major questions remain unresolved concerning how the limbal epithelium is regulated. Likewise, our understanding of factors that control angiogenesis is incomplete. microRNAS (miRNAs) are a major class of regulatory molecules that are part of the RNAi silencing machinery. While some studies have been directed towards deciphering the roles of miRNAs in the corneal epithelium, little is known about the miRNA signature in the stem cell-enriched limbal epithelium. We have recently discovered that miRs-103/107 are limbal-preferred. Furthermore, we have evidence that miRs-103/107 function to insure proper limbal epithelial cell-cell contact, autophagy and impact on cell cycle quiescence. Until recently, it was believed that miR-184, the most abundant corneal epithelial miRNA, functioned to attenuate miR-205, which insured proper cell migration and cell survival. We now have evidence that miR-184 may directly prevent corneal epithelial angiogenesis. Proper vision requires both a stabile limbal epithelial and corneal clarity;therefore we propose to focus on: (1 The roles of miRs-103/107 in assuring the integrity of the limbal epithelium and (2) how miR-184 functions to maintain corneal avascularity. To accomplish these goals, we will capitalize on our ability to elucidate miRNA target proteins and modulate miRNA and target protein levels in submerged cultures of human limbal and corneal epithelial keratinocytes and human microvascular endothelial cells. We will manipulate these cultured cells to form either 3-D organotypic rafts, or endothelial tubes, which mimic the in vivo tissues. We will assess the functional consequences of such miRNA and protein modulations with a combination of biochemical, molecular biological, cell biological and physiological approaches. By focusing on the biology of these miRNAs and their target proteins, our proposal represents a novel approach to understand: (i) how the limbal epithelium is regulated;and (ii) what contributes to the maintenance of corneal avascularity. Such knowledge has relevance to stem cell biology and clinically to ex vivo corneal epithelial transplantation. This proposal also has clinical implicatins beyond just corneal avascularity and may impact on pathological retinal angiogenesis. Ultimately our studies will provide rationales for the development of innovative treatment regimens focused on the use of either: (i) inhibitors of specific miRNAs or their targets;or (ii) delivery of miRNAs in patients with diseases that affect the ocular anterior segmental epithelia.

Public Health Relevance

Information from this project will impact on our understanding of how: (i) the stem cell-enriched limbal epithelium maintains proper cell-cell contacts, autophagy and cell cycle quiescence;properties that are essential for homeostasis;and (ii) the corneal epithelium assures avascularity. The contribution of stem cells to the wellbeing of the corneal epithelium is undeniable as these cells govern self-renewal and tissue regeneration processes. Transparency is essential for proper vision and requires an avascular cornea.

National Institute of Health (NIH)
National Eye Institute (NEI)
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Mckie, George Ann
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Northwestern University at Chicago
Schools of Medicine
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Kaplan, Nihal; Ventrella, Rosa; Peng, Han et al. (2018) EphA2/Ephrin-A1 Mediate Corneal Epithelial Cell Compartmentalization via ADAM10 Regulation of EGFR Signaling. Invest Ophthalmol Vis Sci 59:393-406
Dong, Ying; Peng, Han; Lavker, Robert M (2018) Emerging Therapeutic Strategies for Limbal Stem Cell Deficiency. J Ophthalmol 2018:7894647
Ventrella, Rosa; Kaplan, Nihal; Hoover, Paul et al. (2018) EphA2 Transmembrane Domain Is Uniquely Required for Keratinocyte Migration by Regulating Ephrin-A1 Levels. J Invest Dermatol 138:2133-2143
Wang, Sijia; Kobeissi, Aya; Dong, Ying et al. (2018) MicroRNAs-103/107 Regulate Autophagy in the Epidermis. J Invest Dermatol 138:1481-1490
Cipolla, Gabriel A; Park, Jong Kook; Lavker, Robert M et al. (2017) Crosstalk between Signaling Pathways in Pemphigus: A Role for Endoplasmic Reticulum Stress in p38 Mitogen-Activated Protein Kinase Activation? Front Immunol 8:1022
Peng, Han; Park, Jong Kook; Lavker, Robert M (2017) Autophagy and Macropinocytosis: Keeping an Eye on the Corneal/Limbal Epithelia. Invest Ophthalmol Vis Sci 58:416-423
Park, Jong Kook; Peng, Han; Yang, Wending et al. (2017) miR-184 exhibits angiostatic properties via regulation of Akt and VEGF signaling pathways. FASEB J 31:256-265
Park, Jong Kook; Peng, Han; Katsnelson, Julia et al. (2016) MicroRNAs-103/107 coordinately regulate macropinocytosis and autophagy. J Cell Biol 215:667-685
Cipolla, Gabriel A; Park, Jong Kook; de Oliveira, Liana A et al. (2016) A 3'UTR polymorphism marks differential KLRG1 mRNA levels through disruption of a miR-584-5p binding site and associates with pemphigus foliaceus susceptibility. Biochim Biophys Acta 1859:1306-13
Peng, Han; Park, Jong Kook; Katsnelson, Julia et al. (2015) microRNA-103/107 Family Regulates Multiple Epithelial Stem Cell Characteristics. Stem Cells 33:1642-56

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