Lumican is a major keratan sulfate proteoglycan of the corneal stroma, long suspected and now confirmed to play a pivotal role in corneal transparency. Gene targeted lumican-deficient mice develop abnormally thick and disorganized collagen fibrils in the corneal stroma and consequent corneal opacity. Emerging evidence is now clearly indicating that lumican is regulating stromal cellular functions, and may be a key component of the ECM-to-cell signaling mechanisms. The cellular functions include gene expression, apoptosis, proliferation, attachment and migration, that ultimately impact stromal extracellular matrix (ECM) structure during its development and regeneration after wounding. ? ? The purpose of the current study is to determine the role played by lumican in regulating stromal gene expression and cellular behavior of the keratocytes that synthesize the stromal ECM. The first two aims are directed towards defining lumican's role in regulating keratocyte functions crucial to the development and repair of the stroma.
The first aim will use wild type and lumican-null corneal fibroblasts to investigate lumican's role in regulating apoptosis, proliferation, attachment and migration in culture and determine if TGF beta or EGF mediated pathways are being used.
The second aim will explore its influence on these keratocyte functions in corneal wound healing in vivo.
The third aim will focus on lumican's role in regulating gene expression. The lumican-null corneas will be used to address what stromal components are expressed differently, at the transcript and at protein, levels to explain their thinner stroma and reduced ECM. Finally, the lumican-null mouse phenotype emphasizes lumican as a strong candidate gene for phenotypically similar corneal dystrophies. Certain Cornea plana and corneal dystrophy cases will be screened for lumican mutations. Once such a mutation is detected, the lumican-null mouse will be an animal model of choice to elucidate secondary changes in gene expression that define these broad changes in the cornea. This study will lead to novel insights into lumican's role in regulating cellular functions and provide a fundamental understanding of ECM to cell signaling that affect corneal development, repair and dysfunctions in corneal dystrophies.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY011654-08
Application #
6647716
Study Section
Visual Sciences A Study Section (VISA)
Program Officer
Fisher, Richard S
Project Start
1997-01-01
Project End
2007-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
8
Fiscal Year
2003
Total Cost
$327,000
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Frikeche, Jihane; Maiti, George; Chakravarti, Shukti (2016) Small leucine-rich repeat proteoglycans in corneal inflammation and wound healing. Exp Eye Res 151:142-9
Stasiak, Marta; Boncela, Joanna; Perreau, Corinne et al. (2016) Lumican Inhibits SNAIL-Induced Melanoma Cell Migration Specifically by Blocking MMP-14 Activity. PLoS One 11:e0150226
Hultgårdh-Nilsson, A; Borén, J; Chakravarti, S (2015) The small leucine-rich repeat proteoglycans in tissue repair and atherosclerosis. J Intern Med 278:447-61
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Gowda, Ranjita N; Redfern, Rachel; Frikeche, Jihane et al. (2015) Functions of Peptidoglycan Recognition Proteins (Pglyrps) at the Ocular Surface: Bacterial Keratitis in Gene-Targeted Mice Deficient in Pglyrp-2, -3 and -4. PLoS One 10:e0137129
Steinhart, Matthew R; Cone-Kimball, Elizabeth; Nguyen, Cathy et al. (2014) Susceptibility to glaucoma damage related to age and connective tissue mutations in mice. Exp Eye Res 119:54-60
Foster, James; Wu, Wai-Hong; Scott, Sherri-Gae et al. (2014) Transforming growth factor ? and insulin signal changes in stromal fibroblasts of individual keratoconus patients. PLoS One 9:e106556
Chen, Shoujun; Young, Marian F; Chakravarti, Shukti et al. (2014) Interclass small leucine-rich repeat proteoglycan interactions regulate collagen fibrillogenesis and corneal stromal assembly. Matrix Biol 35:103-11
Chaerkady, Raghothama; Shao, Hanjuan; Scott, Sherri-Gae et al. (2013) The keratoconus corneal proteome: loss of epithelial integrity and stromal degeneration. J Proteomics 87:122-31
Shao, Hanjuan; Scott, Sherri-Gae; Nakata, Chiaki et al. (2013) Extracellular matrix protein lumican promotes clearance and resolution of Pseudomonas aeruginosa keratitis in a mouse model. PLoS One 8:e54765

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