Glaucoma is one of the leading causes of blindness in the world. It affects approximately 66.8 million people worldwide. At least 12,000 Americans are blinded by this disease each year. Recent studies have linked mutations of myocilin, a 55Kd secretory glycoprotein to the pathogenesis of open-angle glaucoma in certain patients. It is believed that accumulation of misfolded mutant myocilins induces cell death in trabecular meshwork (TM), which causes obstruction of TM with increased resistance to aqueous outflow and leads to elevated intraocular pressure with eventual optic nerve damage in open-angle glaucoma. We hypothesize that suppressing the accumulation of mutant myocilin proteins in TM cells, thus preventing cytotoxic effects and cell death, could mitigate myocilin-related open-angle glaucoma. In this proposed research, we will use RNA interference via our custom-designed small interfering RNAs (siRNA; 21-23 nucleotides) to modulate, or suppress, the expression of wild-type and mutant myocilin proteins in cultured 293 and TM cells. The siRNA-mitigated TM cytotoxicity (induced by mutant myocilin) will be studied. We will also explore the feasibility of using a novel nanoencapsulation technology to optimize the delivery of siRNAs into the TM cells for specific suppression of myocilin. Taking advantage of the high specificity of siRNAmediated myocilin suppression and the efficient transfection of nanoencapsulated particles via the ocular surface, this proposal will invesitigate the combination of these two recent scientific breakthroughs, i.e., siRNA and nanoencapsulation, as a potential glaucoma therapy. Results from these experiments will provide the foundation for future animal studies and could help in the development of potential therapeutic modalities for myocilin-related glaucoma or other inherited ocular disorders.
| Grothe, Heather L; Little, Morgan R; Cho, Angela S et al. (2009) Denaturation and solvent effect on the conformation and fibril formation of TGFBIp. Mol Vis 15:2617-26 |
| Huang, Andrew Chih Wei; Hsiao, Sigmund (2008) Re-examination of amphetamine-induced conditioned suppression of tastant intake in rats: the task-dependent drug effects hypothesis. Behav Neurosci 122:1207-16 |
| Yuan, Ching; Zins, Emily J; Clark, Abbott F et al. (2007) Suppression of keratoepithelin and myocilin by small interfering RNAs (siRNA) in vitro. Mol Vis 13:2083-95 |
| Huang, Andrew J W (2007) Suppression of keratoepithelin and myocilin by small interfering RNA (an American Ophthalmological Society thesis). Trans Am Ophthalmol Soc 105:365-78 |
