Discovery and Characterization of Anterior Sclera Pathology in Glaucoma

描述(申请人提供)：原发性开角型青光眼(POAG)采用危险因素管理治疗，唯一可改变的危险因素是眼压(IOP)。以往的生理学研究证实，小梁网是眼部房水流出的主要阻力，并确定POAG的小梁网病变导致眼压升高。同时，TM术后前部巩膜和巩膜内远端流出道的病理改变与TM本身的病变程度几乎相同。这一观察，再加上最近微创青光眼手术(MIG)的不同成功降低眼压，旨在简单地绕过TM，进一步证实了IOP不仅仅是TM。这项名为“青光眼前巩膜病理学的发现和特征”的提案的总体目标是识别新的、揭示其分子机制并认识到在前巩膜和巩膜内远端流出通路中持续阻碍房水流出的重要性。在特定的目标1中，我们将应用现代组织学技术来回顾TM术后巩膜和巩膜内流出通路纤维化和崩溃的先前和初步的建议。在具体目标2中，我们将通过将TM中已知的促纤维化药物如TM中的转化生长因子-B等知识应用于在巩膜管成形术中获得的新鲜青光眼巩膜，来评估巩膜和巩膜内远端流出道纤维化的分子机制。在具体目标3中，我们将通过研究新生青光眼巩膜细胞系的通透性特征和建立新的动物灌流模型，来确定转化生长因子介导的纤维化对巩膜和巩膜内远端流出通路的影响。这个有指导的临床科学家研究职业发展奖是我和所罗门·斯奈德博士在约翰·霍普金斯大学医学院所罗门·斯奈德神经科学系完成医学/博士学位课程的基础和继续，是我在南加州大学多尼眼科研究所接受眼科住院医师培训的基础，也是我在加州大学圣地亚哥分校Robert Weinreb博士指导下的青光眼奖学金的基础。我现在在南加州大学担任眼科学助理教授，因为南加州大学有过往的记录、与K奖获得者的新鲜经验，以及David Hinton博士(导师)、James Tan博士(共同导师)和Robert Weinreb博士(共同导师；在加州大学圣迭戈分校)的出色指导，为我提供必要的额外研究培训和经验，推动我的成功。我的职业发展计划将围绕我的导师和南加州临床与翻译科学研究所组织的年轻研究人员课程和负责任的研究培训。通过这些研究的完成，我们希望(A)进一步了解正常眼房水流出的基本情况，以及(B)对POAG的房水流出障碍有更深入的了解，从而为未来青光眼药物治疗和外科治疗的创新提供依据。此外，通过这种支持，我将实现我的当前目标，即发展我的研究计划和身份，并为我的长期目标确立下一步，即成为一名由NIH独立资助的面向青光眼健康的临床医生兼科学家研究员。

DESCRIPTION (provided by applicant): Primary open angle glaucoma (POAG) is treated by risk factor management for which the only modifiable risk factor is intraocular pressure (IOP). Previous physiologic studies identified the trabecular meshwork (TM) as the primary resistor to aqueous humor outflow from the eye and determined that diseased TM in POAG caused increased IOP. Simultaneously, pathology in the post-TM anterior sclera and intra-scleral distal outflow pathway has been implied with the level of disease here also being nearly equivalent to that of the TM itself. This observation coupled with recent and variably successful IOP lowering from minimally invasive glaucoma surgeries (MIGS), designed to simply bypass the TM, further confirms that IOP is more complex than just the TM. The global goal of this proposal entitled "Discovery and Characterization of Anterior Sclera Pathology in Glaucoma" is to identify novel, uncover the molecular mechanisms of, and realize the importance of continued impediments to aqueous humor outflow downstream of the TM in the anterior sclera and intra-scleral distal outflow pathway. In Specific Aim 1, we will apply modern histological techniques to revisit prior and rudimentary suggestions of post-TM scleral and intra-scleral outflow pathway fibrosis and collapse. In Specific Aim 2, we will evaluate the molecular mechanisms for scleral and intra-scleral distal outflow pathway fibrosis by applying knowledge regarding known pro-fibrotic agents such as TGF-ß in the TM to freshly harvested glaucomatous sclera obtained during canaloplasty surgery. In Specific Aim 3, we will determine the impact of TGF-ß mediated fibrosis on sclera and the intra-scleral distal outflow pathway by studying permeability characteristics via newly generated glaucoma scleral cell lines and by the development of a new animal perfusion model. This Mentored Clinical Scientist Research Career Development Award serves as a foundation and continuation of my MD/PhD completion with Dr. Solomon Snyder at the Solomon Snyder Department of Neuroscience at The Johns Hopkins University School of Medicine, ophthalmology residency training at the Doheny Eye Institute at the University of Southern California (USC), and glaucoma fellowship tutelage under Dr. Robert Weinreb at the University of California, San Diego (UCSD). I have now placed myself at USC as an Assistant Professor in Ophthalmology because USC has the track record, fresh experience with K-awardees, and excellent mentorship in Drs. David Hinton (Mentor), James Tan (Co-Mentor), and Robert Weinreb (Co-Mentor; at UCSD) to provide the additional research training and experience necessary to fuel my success. My career development plan will be built around my mentors and the Southern California Clinical and Translational Science Institute organized young investigator courses and responsible conduct in research training. Through the completion of these studies we hope to (a) further basic understanding of aqueous humor outflow from the normal eye and (b) develop an improved insight into impediments of aqueous humor outflow in POAG to allow for future innovation of pharmacological and surgical glaucoma treatments. Furthermore, through this support, I will achieve my immediate goals of developing my research program and identity as well as establish the next step in my long-term goal of becoming an independently NIH-funded glaucoma health-oriented clinician-scientist researcher.