The Mechanical Basis of Primary Open Angle Glaucoma

原发性开角型青光眼的力学基础

• 批准号: 8323411
• 负责人: MARK JOHNSON
• 金额: $ 77.7万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2014-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8323411
• 关键词: Accounting; Address; Adhesions; Affect; Anterior; Apical; Applications Grants; Aqueous Humor; Architecture; Area; Atomic Force Microscopy; Basement membrane; Behavior; Biochemical; Biological Assay; Biomechanics; Biomedical Engineering; Biophysics; Cell membrane; Cell physiology; Cell-Matrix Junction; Cells; Cellular biology; Chairperson; Characteristics; Computer Simulation; Connective Tissue; Connective Tissue Cells; Cytometry; Cytoskeleton; Data; Disease; Disease Progression; Drops; Elements; Endothelial Cells; Endothelium; Event; Extracellular Matrix; Eye; Gel; Glaucoma; Goals; Health; Human; In Situ; In Vitro; Investigation; Lateral; Liquid substance; Literature; Magnetism; Maps; Measures; Mechanics; Mediating; Mediator of activation protein; Medical Research; Methods; Modeling; Molecular; Ocular Hypertension; Ophthalmology; Optic Nerve; Organ Culture Techniques; Outcome; Pathogenesis; Pathology; Pathway interactions; Perfusion; Permeability; Pharmaceutical Preparations; Physiologic Intraocular Pressure; Physiological; Play; Porosity; Primary Cell Cultures; Primary Open Angle Glaucoma; Process; Property; Regulation; Relaxation; Research; Research Design; Research Personnel; Resistance; Role; Route; Scientist; Signal Transduction; Site; Stress; Stretching; Structure of sinus venosus of sclera; Structure of thyroid parafollicular cell; System; Testing; Time; Tissues; Trabecular meshwork structure; Traction; Universities; Vacuole; Work; anterior chamber; aqueous; base; density; experience; in vivo; multidisciplinary; novel; pressure; programs; public health relevance; research study; response; therapeutic target; tool

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.

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 眼中这种阻力位置的研究表明，大部分流出阻力发生在紧邻施累姆氏管 (SC) 内壁内皮的区域。内壁内皮细胞（SC 细胞）中发现的孔对于穿过内皮的液体运输似乎很重要。我们的团队和其他人发现 POAG 眼的内壁孔隙密度显着降低。这些孔很可能是由于跨内壁内皮的跨细胞压降引起的细胞变形而形成的。如果 SC 细胞变得更硬，那么可能会形成更少的孔隙，可能会导致流出阻力升高。因此，我们假设 POAG 的高眼压特征是由磁扭转细胞术 (MTC)、原子力显微镜 (AFM) 和牵引力显微镜的独特实施例（称为细胞标测流变仪）引起的。这些研究将使我们能够评估这些细胞的刚度及其产生的牵引力。其次，我们将研究 SC 细胞在可拉伸凝胶基质和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生长这些细胞并以基底到顶端方向（生理方向）灌注它们。这些研究将检查 SC 细胞如何响应机械扩张。第三，我们的研究将集中于这些细胞中孔形成的生物力学，以及在去核人眼和器官培养系统中如何通过 SC 细胞硬度来调节这一过程。第四，为了检验流出阻力介质通过涉及 SC 细胞变形和孔形成变化的机械事件发挥作用的假设，我们将使用有限条件，我们将比较正常 C 细胞与青光眼 SC 细胞的生物力学行为。总之，这些目标将使我们能够明确确定 SC 细胞硬度的增加是否会导致内壁孔隙率降低，从而导致大多数 POAG 病例的流出阻力增加。公众健康相关性：大多数青光眼治疗侧重于改变房水形成速率或改变房水流出路径，但不针对导致大多数青光眼病例特征性眼内压升高的患病组织。这些治疗通常会减缓视神经疾病的进展，但通常不能阻止它。如果我们能够确定压力升高的原因，那么我们也许能够开发出更有效的降压疗法或治愈这种使人衰弱的疾病。