Lumican is a major proteoglycan component of the corneal stroma and believed to play a pivotal role in corneal transparency. In the cornea, transparency is combined with tensile strength by a highly ordered array of collagen fibrils of uniformly thin diameter. Lumican inhibits lateral growth of collagen fibrils in vitro and may have a similar effect on collagen fibril formation in the cornea. The keratan sulfate glycosaminoglycan side chains of lumican retain water and help to maintain interfibrillar spacing necessary for transparency. The molecular interactions underlying lumican's influence on collagen fibrils are poorly understood. The PI preliminary results also indicate that lumican is expressed very early in the developing corneal stroma, implying a potential role for this proteoglycan in corneal development. The purpose of this study is to elucidate lumican's role in the cornea.
The first aim i s to define the molecular mechanism underlying lumican's interactions with collagen and gain insight into this important aspect of lumican's function in the cornea.
this aim will determine the binding kinetics and identify sites on the lumican core protein that are active in collagen-binding and inhibiting lateral growth of fibrils.
The second aim i s to determine if lumican inhibits cell adhesion to collagen or fibronectin substrates, and thus, likely to regulate mesenchymal cell adhesion/migration during development of the corneal stroma.
The third aim i s to generate lumican-deficient mice by targeted deletion of the gene for lumican and determine its effect on development of the eye and structure and functions of the cornea. The in vitro experiments proposed in this study will identify functionally important regions of the lumican core protein for future site-directed mutagenesis studies of lumican in vivo. The gene targeted deletion of lumican proposed in this study will, for the first time, address its role in vivo and the overall effect of its absence on the cornea. Generally, the long term objectives are to develop mouse models for corneal dystrophies another connective tissue disorders with altered proteoglycan-collagen matrices.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
7R01EY011654-05
Application #
6414458
Study Section
Visual Sciences A Study Section (VISA)
Program Officer
Fisher, Richard S
Project Start
1997-01-01
Project End
2001-12-31
Budget Start
2000-09-01
Budget End
2000-12-31
Support Year
5
Fiscal Year
2000
Total Cost
$98,467
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
045911138
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
Dupuis, Loren E; Berger, Matthew G; Feldman, Samuel et al. (2015) Lumican deficiency results in cardiomyocyte hypertrophy with altered collagen assembly. J Mol Cell Cardiol 84:70-80
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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