Models, mechanisms and treatment of LMX1B-induced glaucoma

High intraocular pressure (IOP) is a major causal risk factor for glaucoma and is the target of all current glaucoma therapies. Although the importance of the LMX1B genes in human primary open-angle glaucoma (POAG) has clearly been demonstrated, the mechanisms by which LMX1B mutations induce IOP elevation and glaucoma are not known. This project investigates the molecular mechanism by which abnormalities in LMX1B impact IOP and contribute to glaucoma. It will generate a more sophisticated understanding of a human glaucoma gene, ultimately guiding new treatments. Additionally, it will provide well characterized LMX1B glaucoma models to the community. Current IOP-lowering drugs are not effective in many patients, and reduce IOP by no more than 25-30%. Surgery to provide new aqueous humor (AQH) outlets often fails due to scar formation. Therefore, new IOP-lowering therapies are a critical need. New pathways and candidate molecules must be identified to advance development of more potent and specific anti-glaucoma targets. The specific nature of an inherited LMX1B variant is suggested to contribute to differences in glaucoma subtype and disease severity between individuals. We hypothesize that various LMX1B mutations have differential mechanistic effects - affecting LMX1B function or the function of other proteins that interact with LMX1B to regulate transcriptional activity/specificity. Our preliminary data support this hypothesis. We will test our hypothesis in the following aims: Aim 1) Determine the impact of selected Lmx1b mutations on phenotype and protein stability/function. Aim 2): Determine the molecular mechanism by which Lmx1b mutations impact IOP. Aim 3) Determine if Lmx1b impacts cellular metabolism and test a resilience boosting treatment.