Models, mechanisms and treatment of LMX1B-induced glaucoma

高眼内压（IOP）是青光眼的主要致病危险因素，也是所有青光眼患者的目标。 目前青光眼治疗。虽然LMX 1B基因在人类原发性肝癌中的重要性 开角型青光眼（POAG）已被清楚地证明， LMX 1B突变诱导IOP升高和青光眼尚不清楚。该项目调查 LMX 1B异常影响IOP并导致 青光眼它将产生对人类青光眼基因更复杂的理解， 最终指导新的治疗方法。此外，它将提供良好表征的LMX 1B 青光眼模型。目前降低IOP的药物在许多情况下无效。 患者，并降低IOP不超过25- 30%。手术提供新的水状体 (AQH)出口经常由于疤痕形成而失效。因此，新的降眼压疗法是一种 关键的需要。必须确定新的途径和候选分子， 开发更有效和更特异的抗青光眼靶点。一个人的具体性质 遗传性LMX 1B变异被认为是青光眼亚型差异的原因， 个体之间的疾病严重程度。我们假设各种LMX 1B突变 差异机制效应-影响LMX 1B功能或其他蛋白质的功能， 与LMX 1B相互作用以调节转录活性/特异性。我们的初步数据支持 这个假设。我们将在以下目标中测试我们的假设：目标1）确定影响 选择Lmx 1b突变的表型和蛋白质稳定性/功能。目标2：确定 Lmx 1b突变影响IOP的分子机制。目标3）确定Lmx 1b是否 影响细胞新陈代谢并测试恢复力增强治疗。

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.