Development of corneal structure and function is the result of the integration of multiple regulatory pathways converging to produce and maintain a transparent corneal stroma. The overall goals of this application are to elucidate the mechanisms regulating the sequential steps in corneal stroma-specific matrix assembly. A definition of the regulatory steps essential for normal development, growth and maturation provides a foundation for understanding stromal development as well as stromal repair versus regeneration and the potential modulation of these processes. Finally, these studies will address the molecular basis of corneal pathologies, such as cornea plana, corneal stromal congenital dystrophy, and stromal involvement in connective tissue disorders such as Ehlers Danlos Syndrome. Our overall hypothesis is that corneal matrix assembly involves a sequence of events with specific regulatory interactions at each step.
The specific aims of this application are to:
(Aim 1) elucidate the regulatory role(s) of collagen V in fibril assembly, protofibril structure and organization within the developing stroma;
(Aim 2) determine the role(s) of the fibril-associated (FACIT) collagens XII and XIV in mediating protofibril organization and lamellae assembly in the developing stroma;
and (Aim 3) determine the coordinate roles of small leucine-rich proteoglycans (SLRPs) in regulation of corneal fibril growth and packing and elucidate the dysfunctional regulation of matrix assembly in a mouse model of human corneal stroma congenital dystrophy.
The aims are developed around the following hypotheses:
(Aim 1) Nucleation of corneal fibril assembly is regulated by collagen V and this regulation is dependent on developmental stage-specific collagen V isoforms. In addition, collagen V interactions are linked to the keratocyte surface allowing cellular control of fibril organization.
(Aim 2) Stromal compaction, packing of of protofibrils and assembly into developing lamellae are regulated by collagens XII and XIV through their association with the stromal fibrils. This developmental regulation involves a coordinate interaction between collagens XII and XIV.
(Aim 3) Regulation of fibril growth steps and fibril organization involves synergistic regulation by different classes of SLRPs. In addition, the clinical phenotype in human corneal stromal congenital dystrophy is the result of a gain of function mutation involving the C-terminus of the decorin core protein. Mouse models deficient in specific matrix molecules will be utilized to analyze stromal development using biochemical, immunochemical, molecular, morphological and functional approaches. Definition of the regulatory steps in corneal-specific matrix assembly provides the foundation to further our understanding of corneal repair/regeneration, pathobiologies and the manipulation of these processes.
This application will define the mechanisms regulating collagen fibrillogenesis during corneal development, growth and maturation and addresses the molecular basis of the corneal defects in diseases such as type V collagen in classic Ehlers Danlos Syndrome;keratocan in autosomal recessive cornea plana (CNA2);and decorin in congenital stromal dystrophy. In addition, the definition of the mechanisms responsible for cornea-specific extracellular matrix assembly provide a foundation for understanding of corneal repair versus regeneration after wounding or surgical intervention and the modulation of these processes.
|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|
|Smith, Simone M; Birk, David E (2012) Focus on molecules: collagens V and XI. Exp Eye Res 98:105-6|
|Shao, Hanjuan; Chaerkady, Raghothama; Chen, Shoujun et al. (2011) Proteome profiling of wild type and lumican-deficient mouse corneas. J Proteomics 74:1895-905|
|Izu, Yayoi; Sun, Mei; Zwolanek, Daniela et al. (2011) Type XII collagen regulates osteoblast polarity and communication during bone formation. J Cell Biol 193:1115-30|
|Chen, Shoujun; Birk, David E (2011) Focus on molecules: decorin. Exp Eye Res 92:444-5|
|Chen, Shoujun; Sun, Mei; Meng, Xianmin et al. (2011) Pathophysiological mechanisms of autosomal dominant congenital stromal corneal dystrophy: C-terminal-truncated decorin results in abnormal matrix assembly and altered expression of small leucine-rich proteoglycans. Am J Pathol 179:2409-19|
|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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