Phosphoinositide signaling in glaucoma: rescue strategies for Lowe syndrome

摘要 青光眼是导致不可逆转失明的主要原因。降低眼内压（IOP）是 仅有可修改的干预目标，但导致IOP升高的机制仍不清楚 明白这一建议建立在我们对Lowe眼脑肾综合征的研究基础上， 先天性青光眼是X染色体连锁疾病， 孩子OCRL是Lowe综合征中突变的肌醇磷酸酶。本申请旨在 通过靶向肌醇信号传导恢复Lowe综合征的磷酸肌醇失衡 途径。我们已经发现，恢复小梁网中的磷酸肌醇水平 细胞可以挽救Lowe小鼠模型中的疾病。我们已经发现了劳氏综合征患者 他们天生就患有先天性青光眼，并有他们的突变特征。我们还发现 这些患者中的mTOR信号缺陷。因此，我们假设磷酸肌醇的调节 小梁网中的信号传导将恢复房水流出。我们的目标是（1）恢复 通过OCRL的病毒递送的水性流出物，（2）通过抑制上游Pl（4，5）P2平衡过量的Pl（4，5）P2 激酶，（3）在Lowe的小鼠模型和人iPSC模型中调节mTOR信号传导。 综合征我们的工作应该有助于确定OCRL在水流出调节中的作用。以来 磷脂酰肌醇信号转导是IOP控制的新领域，实验应有助于 发现新的青光眼疗法，可以减少失明的负担。

ABSTRACT Glaucoma is a leading cause of irreversible blindness. Lowering intraocular pressure (IOP) is the only modifiable target for intervention, but the mechanisms causing elevated IOP remain poorly understood. This proposal builds on our studies of oculocerebrorenal syndrome of Lowe, a rare X-linked disease that presents with congenital glaucoma, the major cause of blindness in these children. OCRL is an inositol phosphatase mutated in Lowe syndrome. This application seeks to restore the phosphoinositide imbalance that underlies Lowe syndrome by targeting inositol-signaling pathways. We have found evidence that restoring phosphoinositide levels in trabecular meshwork cells can rescue the disease in a Lowe mouse model. We have identified patients with Lowe syndrome who are born with congenital glaucoma and have characterized their mutations. We also discovered mTOR signaling defects in these patients. Thus, we hypothesize that modulation of phosphoinositide signaling in the trabecular meshwork will restore aqueous outflow. Our aims are to (1) restore aqueous outflow by viral delivery of OCRL, (2) balance excess PI(4,5)P2 by inhibiting upstream kinase, (3) modulate mTOR signaling in both the mouse model and a human iPSC model of Lowe syndrome. Our work should help determine the role of OCRL in aqueous outflow regulation. Since phosphoinositide signaling is a novel area of IOP control, the experiments should facilitate discovery of new glaucoma therapies that can reduce the burden of blindness.