The Mechanical Basis of Primary Open Angle Glaucoma

原发性开角型青光眼的力学基础

基本信息

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
项目类别：
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

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

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项目摘要

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）：尚不清楚与主要开放角度青光眼（POAG）相关的水性幽默流出阻力的原因是未知的。旨在确定正常和POAG眼中这种抗性轨迹的研究表明，大部分流出阻力发生在Schlemm的内壁内皮（SC）的内壁内皮附近。内壁内皮细胞（SC细胞）中发现的孔在整个内皮的流体转运中似乎很重要。我们的小组和其他人发现，POAG眼中的内壁孔密度显着降低。这些孔很可能是由于跨内壁内皮跨细胞压降导致细胞变形而形成的。如果SC细胞变得更硬，则可能会形成较少的孔，可能会导致耐药性升高。因此，我们假设POAG的眼部高血压特征是由介绍引起的，包括磁扭曲细胞术（MTC），原子力显微镜（AFM），以及称为细胞映射流变仪的牵引力显微镜的独特实施例。这些研究将使我们能够评估这些细胞的刚度以及它们可以产生的牵引力。其次，我们将研究SC细胞在可伸缩的凝胶底物以及微孔过滤器灌注系统上的行为，该系统使我们能够在滤波器上生长这些细胞并在基础上向根尖方向（生理方向）灌注它们。这些研究将研究SC细胞如何响应机械扩张。第三，我们的研究将重点放在这些细胞中孔形成的生物力学上，以及该过程如何通过浓度的人眼和器官培养系统中的SC细胞刚度调节。第四，为了测试以下假设，即流出阻力的介体通过涉及SC细胞变形和孔形成变化的机械事件发挥其作用，我们将使用有限的数度，我们将比较正常C细胞的生物力学行为与青光眼SC细胞的生物力学行为。总之，这些目标将使我们能够确定SC细胞的刚度增加是否导致内壁孔隙率降低，从而增加大多数POAG病例的流出电阻特征。公共卫生相关性：大多数青光眼治疗方法都集中在改变幽默形成的速度或改变水性幽默流出的路径，但不要针对导致大多数青光眼病例的眼内压力特征升高的患病组织。这些治疗通常会减慢视神经下疾病的进展，但经常不会阻止它。如果我们能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。