Glaucoma is a common blinding disease affecting over 66 million persons worldwide. This project is focused on understanding the molecular mechanism by which laser trabeculoplasty (LTP), a common treatment for glaucoma, lowers intraocular pressure (IOP). Prior studies show that LTP triggers secretion of IL-1beta and TNFalpha by trabecular meshwork (TM) cells. These cytokines then induce matrix metalloproteinase (MMP) expression which initiates extracelluar matrix turnover in the TM. This restores normal outflow resistance and IOP. Several signal transduction pathway have been identified which are essential in this process.
Specific aim 1 is focused on completing the analysis of signaling components and defining the mechanisms involved in increased MMP expression. A new treatment called selective laser trabeculoplasty (SLT) has been developed recently.
Specific aim 2 is focused on comparing the molecular mechanism of action of SLT with the previously defined mechanism of action of argon LTP. The function of myocilin, the first glaucoma gene to be identified, is unknown. Stimuli that trigger TM ECM turnover by the MMPs and reduce IOP, also produce dramatic increases in myocilin expression. Most myocilin binding proteins in the ECM are scaffold or organizing proteins that may be actively involved in the process of ECM turnover.
Specific aim 3 focuses on unraveling the effects of myocilin on binding and turnover of ECM in perfused human anterior segment culture. These studies will expand our understanding of LTP and SLT action and will provide additional potential sites for drug intervention in glaucoma. They will increase our understanding of the ECM turnover process, which is essential for maintaining IOP homeostasis. They will provide information on the role of myocilin in normal and glaucomatous eyes.
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