Cellular Physiology of the Aqueous Outflow Pathway

房水流出途径的细胞生理学

基本信息

  • 批准号:
    8911320
  • 负责人:
  • 金额:
    $ 40.11万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2012
  • 资助国家:
    美国
  • 起止时间:
    2012-09-30 至 2016-08-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Glaucoma is a leading cause of blindness worldwide. A primary risk factor for the development and progression of primary open-angle glaucoma (POAG) is elevation of the intraocular pressure (IOP), resulting from a rise in aqueous humor outflow resistance. To date, the cause of this elevated resistance in POAG remains unknown. Previous studies have shown that the majority of aqueous outflow resistance is localized near the inner wall endothelium of Schlemm's canal (SC) and the juxtacanalicular connective tissue (JCT). Giant vacuoles and pores, which are characteristic features of the endothelial cells of SC, have long been suspected to play a role in regulating outflow resistance. A significant reduction in the number of giant vacuoles and pores was found in POAG eyes. Abnormal accumulations of extracellular matrix (ECM) within the JCT were also found contributing to resistance in POAG, but their contribution to total outflow resistance remains unknown. Our long-term goal is to determine the mechanisms that regulate outflow resistance in normal eyes and how this is increased in POAG. One obstacle in studying outflow resistance is finding a parameter that can be applied to various species regardless of their outflow anatomy. Our group has recently found, in mouse, bovine, monkey and human eyes, that only a fraction of outflow pathways actively contribute to drainage and termed those areas of outflow as the effective filtration area (EFA). We have demonstrated that EFA increases with higher outflow facility after use of a Rho-kinase inhibitor and decreases after acute and chronic elevation of IOP in bovine, monkey and human eyes. Moreover, we found an inverse relationship between IOP and EFA using a hypotensive mouse model. These results suggest that EFA serves as a valuable indicator across varied species for outflow resistance and IOP. We developed a novel fluorophore guided imaging technique to increase our chances of identifying important morphological and cellular differences between areas with high and low flow that contribute to increased outflow resistance and the pathogenesis of POAG. Additionally, we are now able to view giant vacuole formations of SC endothelial cells in real time using a novel three- dimensional cell culture device. With these two novel approaches, we will test our hypothesis that interactions between SC endothelial cells and their underlying ECM modulate giant vacuole and pore formations, thereby regulating EFA and outflow resistance. Our specific aims are too; 1) Evaluate the inverse relationship between the EFA and IOP in ocular hypertensive animal models; 2) Define the inverse relationship between the EFA and the outflow resistance in normal and POAG human eyes and determine the role of SC endothelial cells and their underlying ECM in regulating EFA; 3) Determine the mechanisms by which SC endothelial cells and their underlying ECM regulate the outflow using a novel three-dimensional cell culture device with real-time imaging. The results of this study will provide new insights for a novel therapeutic strategy to lower IOP by targeting the trabecular meshwork, where the initial problem resides.
描述(由申请人提供):青光眼是世界范围内致盲的主要原因。原发性开角型青光眼(POAG)的发展和进展的主要危险因素是眼内压(IOP)升高,这是由房水流出阻力升高引起的。迄今为止,POAG耐药升高的原因尚不清楚。以往的研究表明,大部分的水流出阻力是局部的施累姆氏管(SC)的内壁内皮细胞和睫状小管结缔组织(JCT)。巨空泡和孔是SC内皮细胞的特征性特征,长期以来一直被怀疑在调节流出阻力中起作用。POAG眼内巨大空泡和毛孔数量明显减少。细胞外基质(ECM)在JCT内的异常积累也被发现有助于POAG的阻力,但其对总流出阻力的贡献仍然未知。我们的长期目标是确定调节正常眼外流阻力的机制以及POAG如何增加外流阻力。研究外流阻力的一个障碍是找到一个参数,可以适用于各种物种,而不管他们的外流解剖。我们的研究小组最近发现,在小鼠、牛、猴和人眼中,只有一小部分流出通路积极促进引流,并将这些流出区域称为有效滤过面积(EFA)。我们已经证明,在牛、猴和人眼中,使用Rho激酶抑制剂后,EFA随着流出道功能的增加而增加,而在急性和慢性IOP升高后,EFA则减少。此外,我们发现了一个相反的关系,IOP和EFA使用一个肿胀的小鼠模型。这些结果表明,EFA可作为不同物种外流阻力和IOP的有价值指标。我们开发了一种新型荧光团引导成像技术,以增加识别高流量和低流量区域之间重要形态和细胞差异的机会,这些差异有助于增加流出阻力和POAG的发病机制。此外,我们现在能够使用一种新的三维细胞培养装置在真实的时间内观察SC内皮细胞的巨大空泡形成。通过这两种新的方法,我们将测试我们的假设,即SC内皮细胞和其基础ECM之间的相互作用调节巨空泡和孔的形成,从而调节EFA和流出阻力。我们的具体目标也是; 1)在高眼压动物模型中评价EFA与IOP之间的负相关关系:2)确定正常和POAG人眼中EFA与流出阻力之间的负相关关系,并确定SC内皮细胞及其基础ECM在调节EFA中的作用; 3)使用具有真实的细胞的新型三维细胞培养装置,确定SC内皮细胞及其基础ECM调节流出的机制。时间成像本研究的结果将为通过靶向最初问题所在的小梁网来降低IOP的新治疗策略提供新的见解。

项目成果

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HAIYAN GONG其他文献

HAIYAN GONG的其他文献

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{{ truncateString('HAIYAN GONG', 18)}}的其他基金

Function of Glycocalyx in the Trabecular Outflow Pathway
糖萼在小梁流出通路中的功能
  • 批准号:
    10170361
  • 财政年份:
    2020
  • 资助金额:
    $ 40.11万
  • 项目类别:
Cellular Physiology of the Aqueous Outflow Pathway
房水流出途径的细胞生理学
  • 批准号:
    8723227
  • 财政年份:
    2012
  • 资助金额:
    $ 40.11万
  • 项目类别:
Cellular Physiology of the Aqueous Outflow Pathway
房水流出途径的细胞生理学
  • 批准号:
    8549256
  • 财政年份:
    2012
  • 资助金额:
    $ 40.11万
  • 项目类别:
Cellular Physiology of the Aqueous Outflow Pathway
房水流出途径的细胞生理学
  • 批准号:
    8343543
  • 财政年份:
    2012
  • 资助金额:
    $ 40.11万
  • 项目类别:
Cellular Physiology of the Aqueous Outflow Pathway
房水流出途径的细胞生理学
  • 批准号:
    9383966
  • 财政年份:
    2012
  • 资助金额:
    $ 40.11万
  • 项目类别:
Cellular Physiology of the Aqueous Outflow Pathway
房水流出途径的细胞生理学
  • 批准号:
    9144399
  • 财政年份:
    2012
  • 资助金额:
    $ 40.11万
  • 项目类别:
A Previously Unrecognized Site of Resistance in POAG
POAG 中以前未被识别的耐药位点
  • 批准号:
    7895602
  • 财政年份:
    2009
  • 资助金额:
    $ 40.11万
  • 项目类别:
A Previously Unrecognized Site of Resistance in POAG
POAG 中以前未被识别的耐药位点
  • 批准号:
    7660602
  • 财政年份:
    2009
  • 资助金额:
    $ 40.11万
  • 项目类别:

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