Morphogenesis of cornea, conjunctiva and eyelids during vertebrate eye development involves the migration of mesenchymal cells of neural crest origin and the differentiation of cells of the surface ectoderm. The bi-directional mesenchyme-epithelium interactions via growth factors are essential for morphogenesis during development and homeostasis in adults. TGF-betas and FGF- 7 play pivotal roles in modulating functions of mesenchymal cells of neural crest origin and differentiation of ectoderm cells during ocular morphogenesis. These functions are exemplified by severe clinical manifestations observed as follows: in Tgfb2-/- mice resembling Axenfeld-Reiger's anomaly in human; by biglycan transgenic (KeraprBgn/+) mice of keratocan promoter (Kerapr) exhibiting secondary limbal deficiency; and by FGF-7 transgenic mice of alphaA-crystalline promoter (alphaACpr) resulting in conjunctivalization of corneal surface. These observations raise intriguing questions such as: 1). When do mesenchymal cells commit to becoming endothelial cells? 2). Are eyelid stromal cells also of neural crest origin? 3). What is the role of TGF- beta and FGF-7 signaling in eye development and corneal homeostasis and wound healing? 4). What are the molecular and cellular mechanisms of phenotypes observed in KeraprBgn/+ transgenic mice? To address these questions, we will create tetracycline inducible transgenic mouse models that overexpress the dominant negative mutant of type II TGF-beta receptor, active TGF-beta1 and FGF-7 under the control of Kerapr, and FGF-7 under the control of alphaCApr. With these models we will examine the role of TGF-beta signaling on corneal morphogenesis during development and homeostasis and further characterize the KeraprBgn/+ mice to examine the hypothesis that excess biglycan perturbs TGF-beta signaling during eyelid morphogenesis.
Specific Aim 1 is to elucidate roles of TGF-beta signaling on eye morphogenesis during development, homeostasis and wound healing using tet-O TbetaRIIdn/+ KeraprrtTA/+ and tet-O TGFbeta1/+ KeraprrtTA/+ mice.
Specific Aim 2 will elucidate ocular surface epithelial differentiation using alphaACprrtTA/+ tet-OFGF7/+ and KeraprrtTA/+ tet-OFGF7/+ mice that overexpress FGF-7.
Specific Aim 3 will Elucidate the Role of Excess Biglycan on Eyelid Formation during Development of KeraprBgn/+ mice. The proposed studies will yield useful information for a better understanding of the role of TGF-beta and FGF-7 on corneal development and homeostasis, leading to the design of better treatments for corneal diseases, e.g., epithelial debridement, incision, alkali burn.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY013755-03
Application #
6781086
Study Section
Visual Sciences A Study Section (VISA)
Program Officer
Fisher, Richard S
Project Start
2002-07-01
Project End
2006-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
3
Fiscal Year
2004
Total Cost
$388,559
Indirect Cost
Name
University of Cincinnati
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Call, Mindy; Fischesser, Katy; Lunn, Matthew O et al. (2016) A unique lineage gives rise to the meibomian gland. Mol Vis 22:168-76
Zhang, Yujin; Yeh, Lung-Kun; Zhang, Suohui et al. (2015) Wnt/?-catenin signaling modulates corneal epithelium stratification via inhibition of Bmp4 during mouse development. Development 142:3383-93
Dong, Fei; Liu, Chia-Yang; Yuan, Yong et al. (2015) Perturbed meibomian gland and tarsal plate morphogenesis by excess TGF? in eyelid stroma. Dev Biol 406:147-57
Yuan, Yong; Yeh, Lung-Kun; Liu, Hongshan et al. (2013) Targeted overexpression of TGF-? in the corneal epithelium of adult transgenic mice induces changes in anterior segment morphology and activates noncanonical Wnt signaling. Invest Ophthalmol Vis Sci 54:1829-37
Kao, Winston W-Y; Liu, Hongshan; Zhang, Jianhua (2013) Wakayama symposium: challenges of future research in ocular surface cell biology. Ocul Surf 11:19-24
Ng, Gracia Y; Yeh, Lung-Kun; Zhang, Yujin et al. (2013) Role of SH2-containing tyrosine phosphatase Shp2 in mouse corneal epithelial stratification. Invest Ophthalmol Vis Sci 54:7933-42
Yamanaka, Osamu; Yuan, Yong; Coulson-Thomas, Vivien Jane et al. (2013) Lumican binds ALK5 to promote epithelium wound healing. PLoS One 8:e82730
Zhang, Yujin; Lam, Oliver; Nguyen, Minh-Thanh T et al. (2013) Mastermind-like transcriptional co-activator-mediated Notch signaling is indispensable for maintaining conjunctival epithelial identity. Development 140:594-605
Yuan, Yong; Call, Mindy K; Yuan, Yan et al. (2013) Dexamethasone induces cross-linked actin networks in trabecular meshwork cells through noncanonical wnt signaling. Invest Ophthalmol Vis Sci 54:6502-9
Liu, Hongshan; Zhang, Jianhua; Liu, Chia-Yang et al. (2012) Bone marrow mesenchymal stem cells can differentiate and assume corneal keratocyte phenotype. J Cell Mol Med 16:1114-24

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