Discovery and Characterization of Anterior Sclera Pathology in Glaucoma

描述（由申请人提供）：原发性开角型青光眼（POAG）通过危险因素管理治疗，唯一可改变的危险因素是眼内压（IOP）。先前的生理学研究确定小梁网（TM）是房水流出眼睛的主要阻力，并确定POAG中病变的TM导致IOP升高。同时，TM后前巩膜和巩膜内远端流出通道的病理也被暗示，这里的疾病水平也几乎等同于TM本身。这一观察结果与最近通过微创青光眼手术（MIGS）成功降低IOP的情况相结合，进一步证实IOP比TM更复杂。这项题为“青光眼前巩膜病理学的发现和表征”的提案的总体目标是识别新的，揭示分子机制，并认识到在巩膜前和巩膜内远端流出通道中持续阻碍房水流出的重要性。在具体目标1中，我们将应用现代组织学技术来重新审视tm后巩膜和巩膜内流出通道纤维化和塌陷的先前和初步建议。在Specific Aim 2中，我们将通过将已知的促纤维化剂（如TM中的TGF-ß）的知识应用于在导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通道纤维化的分子机制。在Specific Aim 3中，我们将通过新生成的青光眼巩膜细胞系研究通透性特征，建立新的动物灌注模型，确定TGF-ß介导的纤维化对巩膜及巩膜内远端流出通道的影响。这项指导临床科学家研究职业发展奖是我在约翰霍普金斯大学医学院所罗门·斯奈德神经科学系所罗门·斯奈德博士指导下完成医学博士/博士学位的基础和延续，在南加州大学（USC） Doheny眼科研究所接受眼科住院医师培训，在加州大学圣地亚哥分校（UCSD） Robert Weinreb博士指导下获得青光眼奖学金。我现在在南加州大学担任眼科学助理教授，因为南加州大学有良好的记录，与k奖获得者的新经验，以及在博士方面的优秀指导。David Hinton（导师）、James Tan（联合导师）和Robert Weinreb（加州大学圣地亚哥分校的联合导师）为我提供了额外的研究培训和经验，为我的成功提供了必要的动力。我的职业发展计划将围绕我的导师和南加州临床与转化科学研究所组织的青年研究者课程和负责任的研究培训建立。通过完成这些研究，我们希望(a)进一步了解正常眼房水流出的基本原理，(b)对POAG房水流出的障碍有更深入的了解，从而为未来青光眼药物和手术治疗的创新创造条件。此外，通过这种支持，我将实现我的近期目标，即发展我的研究项目和身份，并建立我的下一步长期目标，即成为一名独立的美国国立卫生研究院资助的青光眼健康导向临床医生科学家研究员。

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.