Redefining the Model of the Blood-Aqueous Barrier

描述（由申请人提供）：在现有的血-房水屏障（BAB）模型中，房水中极低水平蛋白质的升高归因于虹膜血管系统和睫状上皮中紧密连接的渗透性增加。但是，根据我们小组和其他人最近的工作，现在有理由对现有模型的有效性提出质疑。使用我们修改后的BAB模型，我们假设，某些以前报道的临床情况下，其中蛋白质水平上升或下降的房水，可以通过生理机制，而不是病理机制。在拟议的研究中，我们将利用这些情况来挑战我们的BAB新模型的活力。如果我们的新模型被证明是可靠的，它将改变关于晶状体透镜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。待检查的特定事件包括与以下相关的水性蛋白质水平的变化：1）使用抑制房水形成的药物，和2）使用缩瞳剂和散瞳剂。先前的研究无法直接评估眼睛后房中的动力学，因此将每种情况下水性蛋白质水平的变化归因于BAB紧密连接的渗透性改变。使用我们的高分辨率对比磁共振成像方法，可以很容易地识别后房，并可以检测和量化从血流进入的造影剂的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，几乎所有拟议的研究都可以直接在人类志愿者中进行。对人类志愿者的初步研究表明，在新的范式中，正常BAB的动力学可能在男性和女性之间存在差异。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。

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.