RETINAL GANGLION CELL AND AMACRINE CELL FUNCTION IN MOUSE MODELS OF ELEVATED INTR

描述(由申请人提供)：作为贝勒医学院医学科学家培训项目(MSTP)的一员，我的博士论文重点研究眼睛发育的分子遗传学。这项研究导致了许多出版物和奖项，并激励我在约翰·霍普金斯大学的威尔默眼科研究所寻求眼科住院医师资格，并在贝勒医学院获得青光眼研究员学位。在我的培训期间，我一直坚定不移地致力于作为一名临床医生科学家的职业，并计划继续沿着这条道路前进。我的直接职业目标是发展一套新的视网膜神经生理学基本研究技能，加上我之前在遗传学和分子生物学方面的培训，可以用来更好地了解在人类青光眼小鼠模型中发生的视网膜的根本变化。这项培训和研究将作为贝勒医学院眼科系的终身教员，在我选择的导师Samuel M.Wu博士的密切监督下进行。我得到了主席Dan B.Jones医学博士的支持，他提供了实验室空间、资金支持，并充分利用了部门资源，包括NEI视力研究核心助学金。在该奖项的拟议期间，我将加强和延长我作为一名科学家的培训，将我自己在遗传学方面的专业知识与吴博士的视网膜生理知识结合起来，成为一名独特而独立的研究员。我将开始一项专注于青光眼管理的临床眼科实践，将我的研究和临床兴趣联系起来。我的长期职业目标是成为一名独立的调查者，其研究项目专注于描述青光眼疾病的机制。我希望利用这些新信息来开发有洞察力的新翻译应用程序，以增强我们诊断和治疗青光眼的能力。我的研究项目将侧重于提高小鼠眼压(IOP)的影响。初步数据表明，当小鼠眼压升高时，视网膜神经节细胞(RGCs)和AII无长突细胞(AIIAC)在观察到RGC结构变化之前就已经减弱了光反应，AIIAC功能障碍可能是由于视杆介导的信号异常所致。观察到的这些视网膜细胞功能分析的变化可能是青光眼早期视力障碍的基础。利用高眼压的小鼠模型，我计划通过结合免疫组织化学技术、单细胞电压钳制、允许同时采样多个RGC的多电极阵列以及允许对活体小鼠的视力和对比敏感度进行可靠的非侵入性评估的视觉运动系统，建立RGC死亡、RGC光反应和视觉功能的时间表。我还将测试这样一种假设，即AIIAC功能障碍是通过使用类似的技术、加上药理工具和基因敲除小鼠品系的异常杆介导信号而发生的。

DESCRIPTION (provided by applicant): As a member of the medical scientist training program (MSTP) at Baylor College of Medicine, my Ph.D. thesis focused on the molecular genetics of eye development. This research led to a number of publications and awards, and also inspired me to pursue a residency in ophthalmology at the Wilmer Eye Institute at Johns Hopkins and a fellowship in glaucoma at Baylor College of Medicine. During my training I have remained steadfastly committed to a career as a clinician scientist, and plan to continue along this path. My immediate professional goal is to develop a new basic research skill set in retinal neurophysiology which, along with my prior training in genetics and molecular biology, can be used to better understand the fundamental changes to the retina that occur in mouse models of human glaucoma. This training and research will be conducted as a tenure-track faculty member of the Department of Ophthalmology at Baylor College of Medicine, under the close supervision of my chosen mentor, Samuel M. Wu, Ph.D. I have the support of our chairman, Dan B. Jones, M.D. who has provided laboratory space, financial support, and full access to departmental resources including an NEI Core Grant for Vision Research. During the proposed period of the award, I will enhance and extend my training as a scientist, merge my own expertise in genetics with Dr. Wu's knowledge of retinal physiology, and become a unique and independent investigator. I will begin a clinical ophthalmology practice focused on the management of glaucoma, linking my research and clinical interests. My long-term professional goal is to become and an independent investigator whose research program is focused on describing mechanisms of glaucoma disease. I hope to use this new information to develop insightful new translational applications that enhance our ability to diagnose and treat glaucoma. My research project will focus on the effects of intraocular pressure (IOP) elevation in mice. Preliminary data suggest that when IOP is elevated in mice, both retinal ganglion cells (RGCs) and AII amacrine cells (AIIACs) have diminished light responses before any RGC structural changes are observed, and that AIIAC disturbances may occur because of abnormal rod-mediated signaling. The observed changes in these assays of retinal cell function may underlie the early visual disturbances seen in glaucoma. Using mouse models of elevated IOP, I plan to establish a timeline of RGC death, RGC light responses, and visual function through a combination of immunohistochemical techniques, single-cell voltage clamping, multi- electrode arrays which allow for sampling of multiple RGCs simultaneously, and an optomotor system that allows for the reliable non-invasive assessment of both visual acuity and contrast sensitivity in living mice. I will also test the hypothesis that AIIAC dysfunction occurs via abnormal rod-mediated signaling with similar techniques, augmented with pharmacologic tools and knockout mouse strains.