The long-term objectives are to determine the molecular basis of phenotype regulation and define the contributions of the keratocyte, fibroblast and myofibroblast phenotypes to normal corneal biology as well as the response to stromal wounding. A model cell culture system allowing the investigator to reproduce keratocyte to fibroblast and fibroblast to myofibroblast transitions as well as reverse the myofibroblast to fibroblast transition will be utilized. The general hypothesis to be tested in this application is that the three corneal stromal cell phenotypes: keratocyte, fibroblast and myofibroblast are controlled by the interaction of three dominant factors; cell-matrix interactions; cell-cell interactions; and growth factors. The four specific aims will test the hypotheses that: (1) matrix generated signals are essential modulators of the fibroblast/myofibroblast phenotypes. (2) CTGF acts as a matrix signal to influence phenotype, migration and proliferation. (3) uPA and its interaction with transmembrane proteins modulates cellular function. (4) ZO-1 is involved in the fibroblast to myofibroblast transition.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY009414-13
Application #
6697493
Study Section
Special Emphasis Panel (ZRG1-SSS-R (02))
Program Officer
Fisher, Richard S
Project Start
1992-01-01
Project End
2006-12-31
Budget Start
2004-01-01
Budget End
2004-12-31
Support Year
13
Fiscal Year
2004
Total Cost
$423,750
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Yang, Yuanquan; Wang, Zheng; Yang, Hua et al. (2013) TRPV1 potentiates TGF?-induction of corneal myofibroblast development through an oxidative stress-mediated p38-SMAD2 signaling loop. PLoS One 8:e77300
Martignetti, John A; Tian, Lifeng; Li, Dong et al. (2013) Mutations in PDGFRB cause autosomal-dominant infantile myofibromatosis. Am J Hum Genet 92:1001-7
Wang, Lingyan; Ly, Christine M; Ko, Chun-Ying et al. (2012) uPA binding to PAI-1 induces corneal myofibroblast differentiation on vitronectin. Invest Ophthalmol Vis Sci 53:4765-75
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Wang, Lingyan; Ko, Chun-Ying; Meyers, Erin E et al. (2011) Concentration-dependent effects of transforming growth factor ?1 on corneal wound healing. Mol Vis 17:2835-46
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Bernstein, Audrey M; Twining, Sally S; Warejcka, Debra J et al. (2007) Urokinase receptor cleavage: a crucial step in fibroblast-to-myofibroblast differentiation. Mol Biol Cell 18:2716-27
Benezra, Miriam; Greenberg, Roseanne S; Masur, Sandra K (2007) Localization of ZO-1 in the nucleolus of corneal fibroblasts. Invest Ophthalmol Vis Sci 48:2043-9
Greenberg, Roseanne S; Bernstein, Audrey M; Benezra, Miriam et al. (2006) FAK-dependent regulation of myofibroblast differentiation. FASEB J 20:1006-8
Taliana, Lavinia; Benezra, Miriam; Greenberg, Roseanne S et al. (2005) ZO-1: lamellipodial localization in a corneal fibroblast wound model. Invest Ophthalmol Vis Sci 46:96-103

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