Keratan sulfate proteoglycan is one of the major component of the corneal stroma, which composes about 90% of the total corneal thickness, and is important to maintain corneal transparency. Macular corneal dystrophy (MCD) is a hereditary eye disease, of which the patients show spotted opacity in their corneal stroma. The patients eventually need to be subjected to keratoplasty because of blindness by cornea clouding. Based on the studies of a carbohydrate sulfotransferase gene, CHST6, which is responsible for MCD, and the functional analysis of the gene product named human corneal GlcNAc 6-O sulfotransferase (hCGn6ST), we concluded that hCGn6ST is involved in the sulfation of keratan sulfate carbohydrate in the cornea. From these findings, we hypothesize that MCD phenotype is caused by the accumulation of unsulfated keratan sulfate proteoglycan, which is produced by the corneal cells lacking hCGn6ST activity, in the corneal tissue. We also hypothesize the presence of a corneal tissue-specific gene regulatory element(s) in CHST6 and mutations on the element result in the disruption of CHST6 expression in the corneal tissue. To address these issues, we propose the following specific aims; 1) To establish biosynthetic mechanism of corneal keratan sulfate 2) To identify the corneal tissue-specific gene regulatory element in CHST6 3) To produce the gene knockout mouse that is an animal model of MCD in human These results will provide us with information upon the involvement of keratan sulfate carbohydrate in the maintenance of the corneal transparency. Data obtained from this project are expected to form the basis for further clinical applications for MCD and the other corneal diseases through tissue engineering, medication and gene therapy.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-VISA (01))
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Fisher, Richard S
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Sanford-Burnham Medical Research Institute
La Jolla
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Littlechild, Stacy L; Young, Robert D; Caterson, Bruce et al. (2018) Keratan Sulfate Phenotype in the ?-1,3-N-Acetylglucosaminyltransferase-7-Null Mouse Cornea. Invest Ophthalmol Vis Sci 59:1641-1651
Inoue, Tadashi; Ohbayashi, Tetsuya; Fujikawa, Yusuke et al. (2014) Latent TGF-? binding protein-2 is essential for the development of ciliary zonule microfibrils. Hum Mol Genet 23:5672-82
Sugihara, Kazuhiro; Shibata, Toshiaki K; Takata, Kayoko et al. (2013) Attenuation of fibroblast growth factor signaling by poly-N-acetyllactosamine type glycans. FEBS Lett 587:3195-201
Suzuki-Anekoji, Misa; Suzuki, Atsushi; Wu, Sz-Wei et al. (2013) In vivo regulation of steroid hormones by the Chst10 sulfotransferase in mouse. J Biol Chem 288:5007-16
Shibata, Toshiaki K; Matsumura, Fumiko; Wang, Ping et al. (2012) Identification of mono- and disulfated N-acetyl-lactosaminyl Oligosaccharide structures as epitopes specifically recognized by humanized monoclonal antibody HMOCC-1 raised against ovarian cancer. J Biol Chem 287:6592-602
Palka, Barbara P; Sotozono, Chie; Tanioka, Hidetoshi et al. (2010) Structural collagen alterations in macular corneal dystrophy occur mainly in the posterior stroma. Curr Eye Res 35:580-6
Quantock, Andrew J; Young, Robert D; Akama, Tomoya O (2010) Structural and biochemical aspects of keratan sulphate in the cornea. Cell Mol Life Sci 67:891-906
Kitayama, Kazuko; Hayashida, Yasutaka; Nishida, Kohji et al. (2007) Enzymes responsible for synthesis of corneal keratan sulfate glycosaminoglycans. J Biol Chem 282:30085-96
Hiraoka, Nobuyoshi; Petryniak, Bronislawa; Kawashima, Hiroto et al. (2007) Significant decrease in alpha1,3-linked fucose in association with increase in 6-sulfated N-acetylglucosamine in peripheral lymph node addressin of FucT-VII-deficient mice exhibiting diminished lymphocyte homing. Glycobiology 17:277-93
Hayashida, Yasutaka; Akama, Tomoya O; Beecher, Nicola et al. (2006) Matrix morphogenesis in cornea is mediated by the modification of keratan sulfate by GlcNAc 6-O-sulfotransferase. Proc Natl Acad Sci U S A 103:13333-8

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