Autophagy and Mechanotransduction in the Trabecular Meshwork

摘要 小梁网络(TM)是一种位于眼球前段的压敏性组织， 眼内压调节器。该组织的功能障碍导致房水引流不当(AH)。 流出，导致高眼压，这是发展青光眼的主要危险因素。TM由一个 排列着TM内皮样细胞的不规则晶格的胶原梁，跟随着一层松散的结缔组织- 含有TM细胞，AH在离开眼睛之前必须通过这些细胞。压力梯度的变化和 与眼球运动、昼夜节律或眼球脉搏相关的液体流动会引起小的和大的变化 在眼压(IOP)中，它转化为组织变形和松弛的连续循环。 已知TM中的细胞能够将这些变形感知为机械力并对其做出反应 通过引起各种不同的反应。 我们的实验室已经确认了自噬的激活和自噬标记LC3的核转位， 在应用机械拉伸后的TM细胞中。在TM细胞中也观察到自噬的激活 在猪灌流的眼睛和高眼压小鼠模型中，压力升高后迅速。这 促使我们提出自噬是TM细胞对压力的反应中触发的一种重要生理反应 适应机械力，维持细胞动态平衡，在修复和修复过程中发挥双重作用 机械转导。机械传感器的性质，机械信号，以及自噬在体内的确切作用 TM细胞和组织功能尚不清楚。 这个应用程序的目标是研究自噬、初级纤毛和 在TM细胞中的机械转导，并确定这种相互作用在流出途径生理和 病理生理学。更具体地说，我们将检验自噬在TM中起关键作用的假设 通过维持初级纤毛的流行和长度进行的机械转导，以及自噬的失调 随着年龄的增长和青光眼流出道的形成，依赖纤毛的初级眼压稳态受到影响 回应。我们预计，该项目的完成将有助于进一步了解 流出途径组织生理学和病理生理学中的自噬。最相关的是，我们的研究有 寻找治疗高眼压和青光眼的新靶点的可能性。

ABSTRACT The trabecular meshwork (TM) is a pressure sensitive tissue located in the anterior segment of the eye, key regulator of intraocular pressure. Malfunction of this tissue results in improper drainage of aqueous humor (AH) outflow, leading to ocular hypertension, the major risk factor for developing glaucoma. The TM consists of an irregular lattice of collagen beams lined by TM endothelial-like cells, followed a zone of loose connective tissue- containing TM cells, through which AH must pass before leaving the eye. Changes in pressure gradients and fluid flow associated with eye movement, circadian rhythm or the ocular pulse cause small and high variations in intraocular pressure (IOP), which are translated in continuous cycles of tissue deformation and relaxation. Cells in the TM are known to be able of sensing these deformations as mechanical forces and respond to them by eliciting a variety of different responses. Our laboratory has identified activation of autophagy and the nuclear translocation of the autophagy marker LC3, in TM cells following application of mechanical stretch. Activation of autophagy was also observed in TM cells quickly after pressure elevation in porcine perfused eyes and in ocular hypertensive mouse models. This prompted us to propose autophagy as a crucial physiological response triggered in TM cells in response to strain to adapt to mechanical forces and maintain cellular homeostasis, which exerts a dual role in repair and mechanotransduction. The nature of the mechanosensor, mechanosignaling, and exact roles of autophagy in TM cell and tissue function are still not characterized. The goal of this application is to investigate an interplay between autophagy, primary cilium and mechanotransduction in TM cells and to determine the role of such interplay in outflow pathway physiology and pathophysiology. More in particular, we will test the hypothesis that autophagy plays a critical role in TM mechanotransduction by maintaining primary cilia prevalence and length, and that dysregulation of autophagy with aging and in the glaucomatous outflow pathway compromises primary cilia-dependent IOP homeostatic response. We anticipate that completion of this project will contribute to a further understanding of the role of autophagy in outflow pathway tissue physiology and pathophysiology. Most relevant, our studies have the potential of identifying a novel therapeutic target for the treatment of ocular hypertension and glaucoma.