交感神经通过mTORC2/Akt信号通路调控Schlemm管

原发性开角型青光眼（POAG）是全球重大的不可逆致盲性眼病，眼压升高是主要的危险因素。Schlemm管（SC）塌陷是POAG重要改变，调控SC的机制不清。SC的开放状态取决于小梁网张力，而调控小梁网张力的关键在于小梁细胞的肌动蛋白细胞骨架。细胞内mTORC2/Akt信号通路的主要功能即调控细胞骨架。既往发现小梁网有交感神经分布，拟交感神经递质可引起小梁细胞收缩，我们前期研究显示交感神经兴奋伴随SC扩大。由此提出假说：交感神经激活mTORC2/Akt信号通路，促进小梁细胞肌动蛋白多聚化，小梁网张力增加，SC扩大。本项目拟通过原子力显微镜结合小梁网脱细胞模型，明确小梁细胞对小梁网张力的调控；通过刺激或阻断，明确交感神经对小梁网及SC的调控机制；通过siRNA基因敲除及分子干预，明确mTORC2/Akt通路调控小梁细胞肌动蛋白多聚化的分子机制，以期为POAG的发病及治疗提供新机制、新靶点。

Primary open angle glaucoma (POAG) is the first cause of irreversible blindness worldwide, and elevated intraocular pressure is the major risk factor. The collapse of schlemm cannal (SC) is an important change of POAG and the regulatory mechanism of SC maintains unclear. The expansion or shrink of SC depends on the tension of trabecular meshwork, and the trabecular meshwork cell is the key point. Cell tension is mediated by the mTORC2/Akt signal pathway on regulating actin polymorphism, it has been reported sympathetic neurotransmitter receptors were found on trabecular meshwork cells. Our previous studies have shown that sympathetic excitation is associated with SC expansion. We hypothesized that the activation of the mTORC2/Akt signaling pathway after sympathetic excitation could increase the tension of the trabecular meshwork and expand the SC through the actin polymorphism of trabecular cells. This project aims to explore the role of trabecular cells in regulating trabecular mesh tension with de-cellulation model through atomic force microscopy, to explore the mechanism of SC regulation by stimulating or destroying sympathetic nerve in experimental animals, to explore the molecular mechanism of mTORC2/Akt pathway in regulating the actin polymorphism through siRNA gene knockout and signaling pathway intervention, in order to provide a basis for the pathogenesis of POAG and clinical therapy.