The overall goal of this research is to understand the roles of a membrane/soluble glycoprotein complex (Muc4/sialomucin complex, SMC), which is a major contributing mucin at the ocular surface and in the ocular tear film. Muc4/SMC is composed ofa mucin subunit ASGP-1 linked to the plasma membrane via an N-glycosylated transmembrane subunit ASGP-2. The complex is encoded by a single gene, expressed as a 9.2 kb transcript and synthesized as a precursor of approximately 300 kDa. ASGP-1 acts as an anti-recognition factor at cell surfaces. ASGP-2 has two EGF-like domains and can act selectively as a ligand for the receptor tyrosine kinase ErbB2. In addition to the membrane form of Muc4/SMC, corneal epithelia produce a soluble form which is present in tear fluid and loosely associated with the superficial surfaces of the ocular surface epithelia. Our recent studies on transfected cells have shown that Muc4/SMC can act as a repressor of apoptosis and inducer of the cell cycle inhibitor p27kip. Moreover, Muc4/SMC is localized to the most superficial, most differentiated cell layers of the ocular surface epithelia. Our hypothesis is that Muc4/SMC acts to protect ocular surface epithelia by several mechanisms. In recent studies we have established a multilayered cell culture of rat epithelial cells. We will use this culture system to investigate our hypothesis that Muc4/SMC plays an important role in desquamation of cells from the superficial epithelial layer (aim 1). In addition we will develop a transgenic mouse overexpressing and mis-localizing Muc4/SMC in the corneal epithelium to test this hypothesis (aim 1). We will further use a wound healing system and the culture system to investigate the behavior and possible participation of Muc4/SMC in corneal wound healing (aim 2). Finally, we propose to develop a Muc4/SMC knockout mouse for a more comprehensive view of the roles of Muc4/SMC at the ocular surface (aim 3). These combined studies should help to provide us with a more complete picture of the functions of Muc4/SMC at the ocular surface and insights into the roles of this mucin in ocular surface diseases and aberrations.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY012343-06
Application #
6929243
Study Section
Special Emphasis Panel (ZRG1-AED (01))
Program Officer
Fisher, Richard S
Project Start
1998-12-01
Project End
2008-07-31
Budget Start
2005-08-01
Budget End
2006-07-31
Support Year
6
Fiscal Year
2005
Total Cost
$227,250
Indirect Cost
Name
University of Miami School of Medicine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
052780918
City
Miami
State
FL
Country
United States
Zip Code
33146
Lomako, Joseph; Lomako, Wieslawa M; Carothers Carraway, Coralie A et al. (2010) Regulation of the membrane mucin Muc4 in corneal epithelial cells by proteosomal degradation and TGF-beta. J Cell Physiol 223:209-14
Lomako, Wieslawa M; Lomako, Joseph; Soto, Pedro et al. (2009) TGFbeta regulation of membrane mucin Muc4 via proteosome degradation. J Cell Biochem 107:797-802
Theodoropoulos, George; Carraway, Kermit L (2007) Molecular signaling in the regulation of mucins. J Cell Biochem 102:1103-16
Zhang, Jin; Carraway, Coralie A Carothers; Carraway, Kermit L (2006) Muc4 expression during blood vessel formation in damaged rat cornea. Curr Eye Res 31:1011-4
Lomako, Joseph; Lomako, Wieslawa M; Decker, Susan J et al. (2005) Non-apoptotic desquamation of cells from corneal epithelium: putative role for Muc4/sialomucin complex in cell release and survival. J Cell Physiol 202:115-24
Carraway, Kermit L; Ramsauer, Victoria P; Haq, Bushra et al. (2003) Cell signaling through membrane mucins. Bioessays 25:66-71
Swan, Jeremy S; Arango, Maria E; Carothers Carraway, Coralie A et al. (2002) An ErbB2-Muc4 complex in rat ocular surface epithelia. Curr Eye Res 24:397-402
Carraway, Kermit L; Perez, Aymee; Idris, Nebila et al. (2002) Muc4/sialomucin complex, the intramembrane ErbB2 ligand, in cancer and epithelia: to protect and to survive. Prog Nucleic Acid Res Mol Biol 71:149-85
Arango, M E; Li, P; Komatsu, M et al. (2001) Production and localization of Muc4/sialomucin complex and its receptor tyrosine kinase ErbB2 in the rat lacrimal gland. Invest Ophthalmol Vis Sci 42:2749-56
Liu, Z; Carvajal, M; Carraway, C A et al. (2001) Expression of the receptor tyrosine kinases, epidermal growth factor receptor, ErbB2, and ErbB3, in human ocular surface epithelia. Cornea 20:81-5

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