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），之前的生理学研究确定小梁网（TM）是房水的主要阻力。体液从眼睛流出，并确定 POAG 中的患病 TM 引起眼压增加，同时，TM 后前巩膜和巩膜内远端流出的病理学。此处的疾病水平也暗示了 TM 本身的水平几乎相同，这一观察结果加上最近通过微创青光眼手术 (MIGS) 成功降低眼压，旨在简单地绕过 TM，进一步证实了这一点。 IOP 比 TM 更复杂。这项名为“青光眼前巩膜病理学的发现和表征”的提案的全球目标是识别新颖的、揭示其分子机制并认识到持续治疗的重要性。前巩膜和巩膜内远端流出通路中 TM 下游房水流出的障碍 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通路纤维化的先前和基本建议。在具体目标 2 中，我们将通过应用已知的知识来评估巩膜和巩膜内远端流出通路纤维化的分子机制。在特定目标 3 中，我们将通过研究 TGF-β 介导的纤维化对巩膜和巩膜内远端流出途径的影响。通过新产生的青光眼巩膜细胞系和新的动物灌注模型的开发来研究渗透性特征。发展奖是我在约翰·霍普金斯大学医学院所罗门·斯奈德神经科学系跟随所罗门·斯奈德博士完成医学博士/博士学位、在南加州大学多尼眼科研究所进行眼科住院医师培训的基础和延续。在加州大学圣地亚哥分校 (UCSD) 的 Robert Weinreb 博士的指导下，我获得了南加州大学眼科助理教授的指导，因为南加州大学往绩记录、与 K 获奖者的新鲜经验以及 David Hinton 博士（导师）、James Tan（联合导师）和 Robert Weinreb（联合导师；加州大学圣地亚哥分校）的出色指导，提供了额外的研究培训和经验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年轻研究者课程和负责任的研究培训进行，通过完成这些研究，我们希望（a）进一步基础。的理解(b) 更好地了解 POAG 中房水流出的障碍，以便未来进行青光眼治疗的药物和手术创新。此外，通过这种支持，我将实现发展我的近期目标。研究计划和身份，并确定我的长期目标的下一步，即成为一名独立的 NIH 资助的青光眼健康导向的临床医生科学家研究员。