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 #
5R01EY010056-20
Application #
8680235
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
2014-07-01
Budget End
2015-06-30
Support Year
20
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Wilson, Steven E; Marino, Gustavo K; Torricelli, Andre A M et al. (2017) Injury and defective regeneration of the epithelial basement membrane in corneal fibrosis: A paradigm for fibrosis in other organs? Matrix Biol 64:17-26
Santhanam, Abirami; Marino, Gustavo K; Torricelli, Andre A M et al. (2017) EBM regeneration and changes in EBM component mRNA expression in stromal cells after corneal injury. Mol Vis 23:39-51
Marino, Gustavo K; Santhiago, Marcony R; Santhanam, Abirami et al. (2017) Epithelial basement membrane injury and regeneration modulates corneal fibrosis after pseudomonas corneal ulcers in rabbits. Exp Eye Res 161:101-105
Marino, Gustavo K; Santhiago, Marcony R; Torricelli, Andre A M et al. (2016) Corneal Molecular and Cellular Biology for the Refractive Surgeon: The Critical Role of the Epithelial Basement Membrane. J Refract Surg 32:118-25
Torricelli, Andre A M; Santhanam, Abirami; Wu, Jiahui et al. (2016) The corneal fibrosis response to epithelial-stromal injury. Exp Eye Res 142:110-8
Santhanam, Abirami; Torricelli, Andre A M; Wu, Jiahui et al. (2015) Differential expression of epithelial basement membrane components nidogens and perlecan in corneal stromal cells in vitro. Mol Vis 21:1318-27
Torricelli, Andre A M; Marino, Gustavo K; Santhanam, Abirami et al. (2015) Epithelial basement membrane proteins perlecan and nidogen-2 are up-regulated in stromal cells after epithelial injury in human corneas. Exp Eye Res 134:33-8
Schlötzer-Schrehardt, Ursula; Bachmann, Bjoern O; Tourtas, Theofilos et al. (2015) Ultrastructure of the posterior corneal stroma. Ophthalmology 122:693-9
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
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

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