Discovery and Characterization of Anterior Sclera Pathology in Glaucoma

青光眼前巩膜病理学的发现和表征

• 批准号: 9128004
• 负责人: Alex S Huang
• 金额: $ 22.03万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2019-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9128004
• 关键词: Animals; Anterior; Aqueous Humor; Biological Assay; Biomechanics; Blindness; Blood Vessels; Bypass; CD34 gene; California; Cell Line; Cells; Characteristics; Clinical; Clinical Sciences; Collagen; Complex; Coupled; Deposition; Development; Development Plans; Dextrans; Dimensions; Disease; Distal; Doctor of Philosophy; Eye; Fellowship; Fibroblasts; Fibronectins; Fibrosis; Foundations; Funding; Future; Gene Expression; Glaucoma; Goals; Harvest; Health; Histological Techniques; Human; Injection of therapeutic agent; Institutes; K-Series Research Career Programs; Knowledge; Link; Liquid substance; MAP Kinase Gene; Mediating; Mentors; Mentorship; Methods; Modeling; Molecular; Mutant Strains Mice; National Eye Institute; Neurosciences; Operative Surgical Procedures; Ophthalmology; Optic Disk; Optic Nerve; Optics; PECAM1 gene; PI3K/AKT; Pathology; Pathway interactions; Perfusion; Permeability; Physiologic Intraocular Pressure; Physiological; Primary Open Angle Glaucoma; RNA; Reporting; Research; Research Personnel; Research Training; Residencies; Resistance; Risk Factors; Scientist; Sclera; Seminal; Smooth Muscle Actin Staining Method; Source; Suggestion; Techniques; Tissues; Trabecular meshwork structure; Training; Transforming Growth Factor beta; Transgenic Organisms; Translational Research; United States; United States National Institutes of Health; Universities; Vision; Western Blotting; Work; anterior chamber; career development; clinically relevant; clinically significant; design; experience; fluid flow; glaucoma surgery; high intraocular pressure; human tissue; improved; innovation; insight; medical schools; methyl salicylate; minimally invasive; modifiable risk; mouse model; novel; professor; programs; research study; rho; success; tool

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.

描述（由申请人提供）：原发性开角型青光眼（POAG）通过风险因素管理进行治疗，其中唯一可改变的风险因素是眼内压（IOP）。先前的生理学研究确定小梁网（TM）是眼内房水流出的主要阻力，并确定POAG中患病的TM引起IOP升高。同时，TM后前巩膜和巩膜内远端流出通路的病理学已经被暗示，这里的疾病水平也几乎等同于TM本身的水平。这一观察结果与最近成功降低IOP的微创青光眼手术（MIGS）（旨在简单绕过TM）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确定新的、揭示前巩膜和巩膜内远端流出通路中TM下游的房水流出持续障碍的分子机制并认识到其重要性。 在具体目标1中，我们将应用现代组织学技术重新审视TM后巩膜和巩膜内流出道纤维化和塌陷的先前和基本建议。 在具体目标2中，我们将通过将关于已知促纤维化剂（如TM中的TGF-β）的知识应用于在小管成形术期间获得的新鲜收获的青光眼巩膜，来评价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，我们将通过研究经由新产生的青光眼巩膜细胞系的渗透性特征和通过开发新的动物灌注模型来确定TGF-β介导的纤维化对巩膜和巩膜内远端流出途径的影响。 这个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与所罗门斯奈德博士完成的医学博士/博士学位的基础和延续，在南加州大学（USC）的Doheny眼科研究所进行眼科住院医师培训，以及在加州大学Robert Weinreb博士指导下的青光眼奖学金监护，San Diego（UCSD） 我现在已经把自己放在南加州大学作为眼科助理教授，因为南加州大学有良好的记录，与K-获奖者的新鲜经验，并在博士优秀的指导。大卫欣顿（导师），詹姆斯谭（共同导师），和罗伯特Weinreb（共同导师;在UCSD）提供额外的研究培训和必要的经验，以推动我的成功。我的职业发展计划将围绕我的导师和南加州临床和转化科学研究所组织的青年研究者课程和负责任的研究行为培训。 通过完成这些研究，我们希望（a）进一步了解正常眼的房水流出，（B）进一步了解POAG中的房水流出障碍，以便将来创新药物和手术治疗青光眼。此外，通过这种支持，我将实现我的近期目标，发展我的研究计划和身份，以及建立我的长期目标的下一步，成为一个独立的NIH资助的青光眼健康为导向的临床科学家研究员。