The Mechanical Basis of Primary Open Angle Glaucoma

描述（由申请人提供）：与原发性开角型青光眼（POAG）相关的房水流出阻力升高的原因尚不清楚。旨在确定正常和POAG眼睛中这种阻力位置的研究表明，大部分流出阻力发生在Schlemm管（SC）内壁内皮附近。内壁内皮细胞（SC细胞）中发现的孔在通过内皮的流体运输中显得很重要。我们的研究小组和其他研究人员发现，POAG眼的内壁孔密度显著降低。这些孔很可能是对细胞变形的反应，这种变形是由于细胞内壁内皮的跨细胞压降造成的。如果SC细胞变得更硬，那么可能会形成更少的孔，可能会导致流出阻力升高。因此，我们假设POAG的高眼压特征来自于一个介绍，包括磁扭转细胞术（MTC）、原子力显微镜（AFM）和一种独特的牵引力显微镜的体现，称为细胞定位流变术。这些研究将使我们能够评估这些细胞的刚度和它们可以产生的牵引力。其次，我们将研究SC细胞在可拉伸凝胶基质上的行为，以及在微孔过滤器灌注系统中的行为，该系统允许我们在过滤器上培养这些细胞，并将其灌注在从基底到根尖方向（生理方向）。这些研究将检验SC细胞对机械膨胀的反应。第三，我们的研究将集中在这些细胞孔隙形成的生物力学，以及在去核人眼和器官培养系统中SC细胞刚度如何调节这一过程。第四，为了验证流出阻力介质通过涉及SC细胞变形和孔形成变化的机械事件发挥作用的假设，我们将使用有限元素，我们将比较正常C细胞和青光眼SC细胞的生物力学行为。总之，这些目标将使我们能够明确地确定SC细胞刚度的增加是否会导致内壁孔隙率的降低，从而增加大多数POAG病例的流出阻力特征。公共卫生相关性：大多数青光眼治疗的重点是改变房水形成的速度或改变房水流出的路径，但不针对大多数青光眼病例中导致眼压升高的病变组织。这些治疗通常会减缓视神经疾病的进展，但往往不能阻止它。如果我们能够确定血压升高的原因，那么我们可能能够开发出更有效的降压治疗或治愈这种使人衰弱的疾病。

DESCRIPTION (provided by applicant): The cause of the elevated aqueous humor outflow resistance associated with primary open angle glaucoma (POAG) is unknown. Studies aimed at determining the locus of this resistance in both normal and POAG eyes indicate that the bulk of outflow resistance occurs in the immediate vicinity of the inner wall endothelium of Schlemm's canal (SC). Pores found in the inner wall endothelial cells (SC cells) appear important in fluid transport across this endothelium. Our group and others have found that there is a significant reduction of inner wall pore density in POAG eyes. It is likely that these pores are formed in response to cell deformation resulting from the transcellular pressure drop across the inner wall endothelium. If SC cells were to become stiffer, then fewer pores might be expected to form, presumably leading to elevated outflow resistance. Accordingly, we hypothesize that the ocular hypertension characteristic of POAG results from an intro, including magnetic twisting cytometry (MTC), atomic force microscopy (AFM), and a unique embodiment of traction force microscopy called cell mapping rheometry. These studies will allow us to evaluate the stiffness of these cells and the traction forces they can generate. Second, we will investigate the behavior of SC cells on a stretchable gel substrate, and in a microporous filter perfusion system that allows us to grow these cells on a filter and perfuse them in a basal to apical direction (the physiological direction). These studies will examine how SC cells respond to mechanical distension. Third, our studies will focus on the biomechanics of pore formation in these cells and how this process is modulated by SC cell stiffness in enucleated human eyes and in an organ culture system. Fourth, to test the hypothesis that mediators of outflow resistance exert their effects through mechanical events involving changes in SC cell deformation and pore formation, we will use a finite riments, we will compare the biomechanical behavior of normal C cells to those of glaucomatous SC cells. Together, these aims will allow us to definitively determine whether increased stiffness of SC cells leads to a decreased inner wall porosity and consequently the increased outflow resistance characteristic of most cases of POAG. PUBLIC HEALTH RELEVANCE: Most treatments for glaucoma focus on altering the rate of aqueous humor formation or altering the path of aqueous humor outflow, but do not target the diseased tissue responsible for the elevated intraocular pressure characteristic of most cases of glaucoma. These treatments often slow the progression of the disease at the optic nerve, but frequently do not stop it. If we can determine the cause of the elevated pressure, then we may be able to develop a more effective pressure-lowering treatment or cure for this debilitating disease.