The objectives of this proposal are to characterize the mechanisms involved in the tissue-specific assembly of corneal extracellular matrices. Specific interactions regulate fibrillogenesis and matrix assembly during development. Corneal-specific extracellular matrix assembly is a multistep process and the coordinate regulation of the individual steps is essential for normal development and growth. The acquisition of this foundation will provide the basis for understanding of repair/regeneration, pathobiology and eventually permit the modulation of these processes.
The specific aims of this project are: (1) to characterize the specific steps in corneal fibrillogenesis regulated by collagen type I/V interactions; (2) to determine the role of the leucine-rich repeat proteoglycans, decorin and lumican, in corneal fibril and matrix assembly; and (3) to analyze keratocyte-matrix interactions in regulation of tissue-specific matrix assembly and cell behavior. We will utilize transgenic mice deficient in type V collagen, type VI collagen, decorin or lumican with structural, morphometric, molecular, biochemical and immunochemical approaches. Our hypothesis is that during the initial assembly of collagen molecules into the corneal fibril, type V collagen nucleates initial fibril assembly and that the high concentration of type V collagen in heterotypic fibrils favors initiation of new fibrils rather that continued growth of existing fibrils. We hypothesize that the temporal and spatial expression patterns of leucine-rich repeat proteoglycans confer developmental stage-specific interactions that regulate different steps in fibrillogenesis and also are important in mediating higher order matrix assembly. We hypothesize that interactions with the developing extracellular matrix determine keratocyte topography and orientation. This ultimately determines how specific stages in matrix assembly are compartmentalized within the developing stroma. Factors that influence cell behavior would be expected to have a profound effect on the cell's ability to regulate extracellular events. An understanding of corneal development, transparency, hydration, as well as disorders such as edema, wound healing and some dystrophies requires the elucidation of the factors involved in the regulation of collagen fibrillogenesis, matrix assembly and tissue interactions. The proposed studies will lead to an understanding of these processes.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Study Section
Visual Sciences A Study Section (VISA)
Program Officer
Fisher, Richard S
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Thomas Jefferson University
Schools of Medicine
United States
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Chen, Shoujun; Mienaltowski, Michael J; Birk, David E (2015) Regulation of corneal stroma extracellular matrix assembly. Exp Eye Res 133:69-80
Espana, Edgar M; Sun, Mei; Birk, David E (2015) Existence of Corneal Endothelial Slow-Cycling Cells. Invest Ophthalmol Vis Sci 56:3827-37
Basu, Sayan; Hertsenberg, Andrew J; Funderburgh, Martha L et al. (2014) Human limbal biopsy-derived stromal stem cells prevent corneal scarring. Sci Transl Med 6:266ra172
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
Chen, Shoujun; Birk, David E (2013) The regulatory roles of small leucine-rich proteoglycans in extracellular matrix assembly. FEBS J 280:2120-37
Hemmavanh, Chinda; Koch, Manuel; Birk, David E et al. (2013) Abnormal corneal endothelial maturation in collagen XII and XIV null mice. Invest Ophthalmol Vis Sci 54:3297-308
Chen, Shoujun; Sun, Mei; Iozzo, Renato V et al. (2013) Intracellularly-retained decorin lacking the C-terminal ear repeat causes ER stress: a cell-based etiological mechanism for congenital stromal corneal dystrophy. Am J Pathol 183:247-56
Chervoneva, Inna; Zhan, Tingting; Iglewicz, Boris et al. (2012) Two-stage hierarchical modeling for analysis of subpopulations in conditional distributions. J Appl Stat 39:445-460
Smith, Simone M; Birk, David E (2012) Focus on molecules: collagens V and XI. Exp Eye Res 98:105-6
Sun, Mei; Chen, Shoujun; Adams, Sheila M et al. (2011) Collagen V is a dominant regulator of collagen fibrillogenesis: dysfunctional regulation of structure and function in a corneal-stroma-specific Col5a1-null mouse model. J Cell Sci 124:4096-105

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