Phosphoinositide signaling in glaucoma: rescue strategies for Lowe syndrome

摘要 青光眼是导致不可逆性失明的主要原因。降低眼压(IOP)是 只有可修改的干预目标，但导致高眼压的机制仍然很差 明白了。这一建议建立在我们对一种罕见的洛氏眼脑肾综合征的研究基础上。 X连锁疾病，表现为先天性青光眼，是这些人失明的主要原因 孩子们。OCRL是一种在Lowe综合征中突变的肌醇磷酸酶。此应用程序旨在 通过靶向肌醇信号通路恢复导致Lowe综合征的肌醇磷脂失衡 小路。我们发现有证据表明，恢复小梁网中的肌醇磷脂水平 细胞可以在Lowe小鼠模型中拯救这种疾病。我们已经确定了洛威综合征的患者 这些人出生时就患有先天性青光眼，并具有突变的特征。我们还发现 这些患者的mTOR信号缺陷。因此，我们假设肌醇磷脂的调节作用 小梁网络中的信号将恢复房水流出。我们的目标是(1)恢复 通过病毒传递OCRL的房水流出，(2)通过抑制上游来平衡过量的PI(4，5)P2 激酶，(3)调节LOWE小鼠模型和人IPSC模型中的mTOR信号 综合症。我们的工作应该有助于确定OCRL在房水流出调节中的作用。自.以来 肌醇磷脂信号是眼压控制的一个新领域，实验应该有助于 发现可以减轻失明负担的青光眼新疗法。

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.