The Mechanical Basis of Primary Open Angle Glaucoma

描述(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。旨在确定正常眼和POAG眼的这种阻力位置的研究表明，大部分流出阻力发生在Schlemm管(SC)内壁内皮细胞的附近。在内壁内皮细胞(SC细胞)中发现的小孔在流体通过该内皮细胞的运输中似乎很重要。我们的团队和其他人发现，POAG眼的内壁孔道密度显著降低。这些毛孔很可能是由于细胞变形而形成的，这些变形是由于跨内壁内皮的跨细胞压降造成的。如果干细胞变得更硬，那么可能会形成更少的气孔，可能会导致流出阻力增加。因此，我们假设POAG的高眼压特征是由一种介绍引起的，包括磁扭转细胞术(MTC)、原子力显微镜(AFM)和牵引力显微镜的独特体现称为细胞映射流变学。这些研究将使我们能够评估这些电池的硬度和它们可以产生的牵引力。其次，我们将研究干细胞在可伸展凝胶基质上的行为，以及在微孔过滤器灌流系统中的行为，微孔过滤器灌流系统允许我们在过滤器上生长这些细胞，并沿从底部到顶端的方向(生理方向)灌流它们。这些研究将检验干细胞对机械扩张的反应。第三，我们的研究将集中在这些细胞中孔形成的生物力学，以及在去核的人眼和器官培养系统中，这一过程如何受到SC细胞硬度的调节。第四，为了验证流出阻力介质通过涉及SC细胞变形和孔洞形成变化的力学事件发挥作用的假设，我们将使用有限的实验，我们将比较正常C细胞和青光眼SC细胞的生物力学行为。综上所述，这些目标将使我们最终确定干细胞硬度的增加是否会导致内壁孔隙率的减少，从而增加大多数POAG病例的流出阻力特征。与公众健康相关：大多数青光眼的治疗集中在改变房水形成的速度或改变房水流出的路径，但并不针对导致大多数青光眼患者眼压升高的病变组织。这些治疗方法通常会减缓视神经疾病的发展，但往往不能阻止疾病的发展。如果我们能确定血压升高的原因，那么我们可能就能开发出一种更有效的降压疗法或治愈这种令人衰弱的疾病。

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.