Redefining the Model of the Blood-Aqueous Barrier

重新定义血水屏障模型

• 批准号: 6545006
• 负责人: Thomas Frank Freddo
• 金额: $ 33.15万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6545006
• 关键词: Primates; biological models; blood aqueous barrier; blood vessels; clinical research; gender difference; human subject; immunocytochemistry; intraocular aqueous flow; iris; laboratory rabbit; magnetic resonance imaging; mathematical model; membrane permeability; noninvasive diagnosis; protein transport; tight junctions; uvea ciliary body

DESCRIPTION (provided by applicant): In the existing model of the blood-aqueous barrier (BAB), elevations in the very low levels of protein in the aqueous humor are attributed to increased permeability of the tight junctions in the iris vasculature and ciliary epithelium. But, based upon recent work by our group and others, there is reason to now challenge the validity of the present model. Using our revised model of the BAB, we hypothesize that certain previously reported clinical circumstances, in which protein levels rise or fall in aqueous humor, can be accounted for via physiological rather than pathological mechanisms. In the proposed studies, we will exploit each of these circumstances to challenge the vigor of our new model of the BAB. If our new model proves robust, it would change fundamental assumptions about the biological environment surrounding the crystalline lens and within the trabecular meshwork. These changes have potential implications in the pathobiology of cataract and glaucoma. The particular events to be examined include changes in aqueous protein levels associated with: 1) the use of medications that suppress aqueous humor formation, and 2) the use of miotics and mydriatics, Previous studies suffered from an inability to DIRECTLY assess kinetics in the posterior chamber of the eye and thus attributed changes in aqueous protein levels in each instance to altered permeability of the BAB's tight junctions. Using our high-resolution, contrast magnetic resonance imaging methods, the posterior chamber can be readily identified and changes in the amount and time-course of contrast material entering from the bloodstream can be detected and quantified. Most importantly, because these methods are non-invasive, nearly all of the proposed studies can be done directly in human volunteers. Preliminary studies in human volunteers suggest that the kinetics of the normal BAB in the new paradigm may differ between men and women. Thus, we will attempt to confirm and explain this observation and also look for changes in kinetics with age. We will use computational modeling of barrier kinetics to corroborate our experimental observations.

描述（由申请人提供）：在现有的血水屏障（BAB）模型中，房水中极低水平蛋白的升高是由于虹膜脉管系统和睫状上皮紧密连接的通透性增加。但是，根据我们小组和其他人最近的工作，现在有理由挑战当前模型的有效性。使用我们修订的BAB模型，我们假设某些先前报道的临床情况，其中房水中蛋白质水平上升或下降，可以通过生理机制而不是病理机制来解释。在建议的研究中，我们将利用这些情况来挑战我们的新模式的活力。如果我们的新模型被证明是可靠的，它将改变关于晶状体周围和小梁网内生物环境的基本假设。这些变化在白内障和青光眼的病理生物学中具有潜在的意义。要检查的特殊事件包括与以下因素相关的水蛋白水平的变化：1)使用抑制房水形成的药物，2)使用模拟物和静脉血。先前的研究无法直接评估眼后房的动力学，因此将每种情况下水蛋白水平的变化归因于BAB紧密连接通透性的改变。使用我们的高分辨率磁共振成像方法，可以很容易地识别后房，并且可以检测和量化从血液进入的造影剂的数量和时间过程的变化。最重要的是，由于这些方法是非侵入性的，几乎所有提出的研究都可以直接在人类志愿者身上进行。在人类志愿者中进行的初步研究表明，在新范式下，正常的BAB动力学在男性和女性之间可能有所不同。因此，我们将试图证实和解释这一观察结果，并寻找动力学随年龄的变化。我们将使用势垒动力学的计算模型来证实我们的实验观察。