Aqueous Humor Dynamic Components that Determine Intraocular Pressure Variance

描述(申请人提供)：青光眼是导致失明的主要原因。无法预测患者的眼压对药物的反应是临床医生持续提供高效的基于眼压的治疗的关键障碍。目前青光眼治疗的反复试验方法是低效的，并且没有解决这个障碍，因为没有药物反应的预测因素。我们的长期目标是通过识别生物标志物和环境因素来改善结果，这些生物标志物和环境因素根据发病年龄、疾病进展速度、对治疗的“不良反应”和较大的眼压波动来描述青光眼风险患者。我们的目标是通过专注于预测眼压对药物反应的生理因素来解决这一关键障碍。我们的中心假设是，个体房水动态成分预测眼压对药物的反应。我们将通过两个目标来检验中心假设，从而实现我们的目标并朝着我们的目标努力。目的1：验证房水流入是个体间硫吗心安介导的眼压反应变化的生理标志物的假设。目的2：验证房水流出是拉坦前列素介导的个体间眼压反应变化的生理标志物的假设。总体实验设计将是对同一个体在未治疗的对照条件下和在使用两种最常用的药物类别的治疗的实验条件下的眼压的生理成分进行全面比较，这两类药物分别是β-受体阻滞剂(目标1)和前列腺素(目标2)。主要的观察指标是眼压的生理成分，即房水流入、流出设施、巩膜上静脉压和葡萄膜巩膜流出。这四个生理成分与眼压之间的关系将通过广义线性模型进行分析。这些结果将为同一队列中基线和治疗条件下眼压的生理成分提供一个急需的数据库。我们的团队致力于通过研究高眼压患者和早期开角型青光眼患者，将这些广泛的生理学数据从对照组发展到下一阶段。这样的模型将形成未来研究的基础，以调查分子和环境相互作用对基于眼压的治疗结果和新的治疗靶点的影响。我们的结果将通过解剖个体之间药物反应差异的生理成分来促进对药物反应差异的理解。这一知识将使我们更接近于预测治疗效果，并通过事先确定哪些患者反应不佳来减少治疗失败。根据患者的药物反应情况开药将消除浪费在无效药物处方上的时间，并导致更有效的医疗管理，更少的后续办公室访问以评估不良疗效。

DESCRIPTION (provided by applicant): Glaucoma is a major cause of blindness. The inability to predict a patient's IOP response to medications is a critical barrier for the clinician to consistently provide highly effective IOP-based treatments. Current trial-and- error approaches to glaucoma management are inefficient and have not addressed this barrier as there are no predictive factors for drug response. Our long-term goal is to improve outcomes by identifying biomarkers and environmental factors that profile a patient at risk for glaucoma by age-of-onset, rate of disease progression, "poor response" to treatment, and large IOP fluctuation. Our objective is to address this critical barrier by focusing on physiological factors that predict IOP response to drugs. Our central hypothesis is that individual aqueous humor dynamic components predict IOP response to medications. We will achieve our objective and work toward our goal by testing the central hypothesis through two aims. Aim 1: Test the hypothesis that aqueous humor inflow is a physiological marker of variation in timolol-mediated IOP response between individuals. Aim 2: Test the hypothesis that aqueous humor outflow is a physiological marker of variation in latanoprost-mediated IOP response between individuals. The overall experimental design will be a comprehensive comparison of physiological components of IOP in the same individual under control conditions without treatment and under experimental conditions with treatment using the two most commonly used drug classes, beta-blockers (Aim 1) and prostaglandins (Aim 2). The main outcome measures are the physiological components of IOP, namely, aqueous humor inflow, outflow facility, episcleral venous pressure, and uveoscleral outflow. The relationships among these four physiological components to IOP will be analyzed by generalized linear models. These results will provide a critically needed database on physiological components of IOP under baseline and treated conditions in the same cohort. Our team is committed to build upon these extensive physiology data from controls to the next phase by studying patients with ocular hypertension and early stages of open-angle glaucoma. Such a model would form the basis for future studies to investigate molecular and environmental interactions on IOP-based treatment outcomes and new therapeutic targets. Our results will advance understanding of IOP response variance to medications by dissecting the physiological components of drug response variations between individuals. This knowledge will bring us closer to predicting therapeutic efficacy, and decreasing treatment failures by identifying patients who are poor responders a priori. Prescribing medications based on a patient's profile of drug response will eliminate time wasted on ineffective drug prescriptions and result in more efficient medical management with fewer follow-up office visits to assess poor efficacy.