Role of Lumican in the Cornea

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Lumican is a major keratan sulfate proteoglycan of the corneal stroma, long suspected and now confirmed to play a pivotal role in corneal transparency. Gene targeted lumican-deficient mice develop abnormally thick and disorganized collagen fibrils in the corneal stroma and consequent corneal opacity. Emerging evidence is now clearly indicating that lumican is regulating stromal cellular functions, and may be a key component of the ECM-to-cell signaling mechanisms. The cellular functions include gene expression, apoptosis, proliferation, attachment and migration, that ultimately impact stromal extracellular matrix (ECM) structure during its development and regeneration after wounding. The purpose of the current study is to determine the role played by lumican in regulating stromal gene expression and cellular behavior of the keratocytes that synthesize the stromal ECM. The first two aims are directed towards defining lumican's role in regulating keratocyte functions crucial to the development and repair of the stroma. The first aim will use wild type and lumican-null corneal fibroblasts to investigate lumican's role in regulating apoptosis, proliferation, attachment and migration in culture and determine if TGF beta or EGF mediated pathways are being used. The second aim will explore its influence on these keratocyte functions in corneal wound healing in vivo. The third aim will focus on lumican's role in regulating gene expression. The lumican-null corneas will be used to address what stromal components are expressed differently, at the transcript and at protein, levels to explain their thinner stroma and reduced ECM. Finally, the lumican-null mouse phenotype emphasizes lumican as a strong candidate gene for phenotypically similar corneal dystrophies. Certain Cornea plana and corneal dystrophy cases will be screened for lumican mutations. Once such a mutation is detected, the lumican-null mouse will be an animal model of choice to elucidate secondary changes in gene expression that define these broad changes in the cornea. This study will lead to novel insights into lumican's role in regulating cellular functions and provide a fundamental understanding of ECM to cell signaling that affect corneal development, repair and dysfunctions in corneal dystrophies.