The broad, long term objectives of this study are to (I) identify and characterize the growth factor-receptor systems through which the functions of corneal, immune, and other cells of the anterior segment of the eye are controlled during development, homeostasis, and wound healing;(II) understand at the molecular and cellular level, the factors that lead to corneal opacity and its resolution after excimer laser surface ablation procedures;(III) explore the importance of the epithelial basement membrane in modulating epithelial-stromal interactions in the cornea.
The Specific aims of this proposal are to test the hypotheses that 1) development of mature vimentin+/?-smooth muscle actin+/desmin+ (V+A+D+) myofibroblasts from corneal stromal or bone marrow- derived precursor cells is regulated by the coordinated, sequential action of TGF? and PDGF, 2a) myofibroblast development can be modulated in vitro by TGF? and PDGF, 2b) myofibroblast development in vitro follows a similar developmental pathway of marker expression as it does in vivo, 2c) small molecules that interfere with TGF? and/or PDGF signaling can be used to modulate i) myofibroblast generation in vitro and ii) myofibroblast generation and stromal opacity in vivo, and 3a) IL-1 produced in the stroma to regulate myofibroblast viability in vivo after haze generating corneal surgery is expressed via autocrine IL-1 production by the myofibroblasts themselves and 3b) that knockout of IL-1 receptor, type I, in mice results in an augmented stromal haze and myofibroblast response to injury and myofibroblast persistence over time. These studies are likely to lead to better and safer treatments to prevent sight damaging stromal opacity that frequently occurs after surgical procedures on the cornea. It may also lead to treatments to increase scaring in the cornea where it is beneficial, for example at the donor-recipient junction in corneal transplantation.

Public Health Relevance

The health relatedness of this project is that it is likely to (i) lead to better pharmacological control of wound healing following surgery or injury to the cornea;and (ii) provide a better understanding of the pathogenesis and treatment or scarring that occurs after corneal surgery. The research design is histopathological, cellular, and molecular investigations in corneas and cultured cells from animal models.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY010056-19
Application #
8518325
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Mckie, George Ann
Project Start
1994-08-01
Project End
2015-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
19
Fiscal Year
2013
Total Cost
$357,960
Indirect Cost
$129,960
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Singh, Vivek; Jaini, Ritika; Torricelli, André A M et al. (2014) TGF? and PDGF-B signaling blockade inhibits myofibroblast development from both bone marrow-derived and keratocyte-derived precursor cells in vivo. Exp Eye Res 121:35-40
Singh, Vivek; Barbosa, Flavia L; Torricelli, Andre A M et al. (2014) Transforming growth factor ? and platelet-derived growth factor modulation of myofibroblast development from corneal fibroblasts in vitro. Exp Eye Res 120:152-60
Torricelli, Andre A M; Wilson, Steven E (2014) Cellular and extracellular matrix modulation of corneal stromal opacity. Exp Eye Res 129:151-60
Singh, Vivek; Torricelli, Andre A M; Nayeb-Hashemi, Neema et al. (2013) Mouse strain variation in SMA(+) myofibroblast development after corneal injury. Exp Eye Res 115:27-30
Singh, Vivek; Jaini, Ritika; Torricelli, Andre A M et al. (2013) A method to generate enhanced GFP+ chimeric mice to study the role of bone marrow-derived cells in the eye. Exp Eye Res 116:366-70
Torricelli, Andre A M; Singh, Vivek; Santhiago, Marcony R et al. (2013) The corneal epithelial basement membrane: structure, function, and disease. Invest Ophthalmol Vis Sci 54:6390-400
Torricelli, Andre A M; Singh, Vivek; Agrawal, Vandana et al. (2013) Transmission electron microscopy analysis of epithelial basement membrane repair in rabbit corneas with haze. Invest Ophthalmol Vis Sci 54:4026-33
Wilson, Steven E (2012) Corneal myofibroblast biology and pathobiology: generation, persistence, and transparency. Exp Eye Res 99:78-88
Santhiago, Marcony R; Wilson, Steven E (2012) Cellular effects after laser in situ keratomileusis flap formation with femtosecond lasers: a review. Cornea 31:198-205
Singh, V; Agrawal, V; Santhiago, M R et al. (2012) Stromal fibroblast-bone marrow-derived cell interactions: implications for myofibroblast development in the cornea. Exp Eye Res 98:1-8

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