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。旨在确定正常眼和POAG眼的阻力轨迹的研究表明，大部分流出阻力发生在施累姆氏管（SC）的内壁内皮附近。在内壁内皮细胞（SC细胞）中发现的孔在穿过该内皮的流体运输中显得重要。我们的研究小组和其他人发现POAG眼的内壁孔密度显著降低。很可能这些孔是响应于细胞变形而形成的，所述细胞变形由穿过内壁内皮的跨细胞压降引起。如果SC细胞变得更硬，那么可能会形成更少的孔，可能导致流出阻力升高。因此，我们假设POAG的高眼压特征是由一种介绍引起的，包括磁扭曲细胞术（MTC）、原子力显微镜（AFM）和一种称为细胞绘图流变学的牵引力显微镜的独特实施方案。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以基底到顶端方向（生理方向）灌注它们。这些研究将研究SC细胞如何对机械扩张做出反应。第三，我们的研究将集中在这些细胞中孔形成的生物力学，以及这个过程是如何在去核的人眼和器官培养系统中由SC细胞刚度调制的。第四，为了检验流出阻力介质通过涉及SC细胞变形和孔形成的变化的机械事件发挥其作用的假设，我们将使用有限的时间，我们将比较正常C细胞与肿瘤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是否增加刚度的SC细胞导致内壁孔隙率降低，从而增加外流阻力的POAG的大多数情况下的特点。公共卫生相关性：青光眼的大多数治疗集中于改变房水形成的速率或改变房水流出的路径，但不靶向导致大多数青光眼病例的眼内压升高特征的患病组织。这些治疗通常会减缓视神经疾病的进展，但通常不会阻止它。如果我们能够确定压力升高的原因，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.