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计划（MSTP）的成员，我的博士学位。本论文的重点是眼睛发育的分子遗传学。这项研究导致了一些出版物和奖项，也激励我在约翰霍普金斯的威尔默眼科研究所从事眼科住院医师工作，并在贝勒医学院获得青光眼研究员资格。在我的培训期间，我一直坚定地致力于临床科学家的职业生涯，并计划继续沿着这条道路。我的近期职业目标是发展一种新的视网膜神经生理学基础研究技能，沿着我之前在遗传学和分子生物学方面的培训，可以用来更好地理解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职员工进行，在我选择的导师塞缪尔M。吴博士我得到了我们主席丹B的支持。Jones，医学博士谁提供了实验室空间，财政支持，并充分利用部门资源，包括NEI核心拨款的视觉研究。在获奖期间，我将加强和扩展我作为科学家的培训，将我自己在遗传学方面的专业知识与吴博士在视网膜生理学方面的知识相结合，成为一名独特而独立的研究者。我将开始临床眼科实践，重点是青光眼的管理，连接我的研究和临床利益。 我的长期职业目标是成为一名独立的研究者，其研究项目集中在描述青光眼疾病的机制。我希望利用这些新的信息来开发有见地的新的翻译应用程序，提高我们诊断和治疗青光眼的能力。 我的研究项目将集中在眼内压（IOP）升高对小鼠的影响。初步数据表明，当小鼠IOP升高时，在观察到任何RGC结构变化之前，视网膜神经节细胞（RGC）和AII无长突细胞（AIIAC）的光反应均减弱，并且由于异常的视杆细胞介导的信号传导，可能会发生AIIAC紊乱。在这些视网膜细胞功能测定中观察到的变化可能是青光眼中观察到的早期视力障碍的基础。使用IOP升高的小鼠模型，我计划通过免疫组织化学技术、单细胞电压箝位、允许同时对多个RGC进行采样的多电极阵列和允许对活小鼠的视敏度和对比敏感度进行可靠的非侵入性评估的视动系统的组合来建立RGC死亡、RGC光反应和视觉功能的时间轴。我还将测试的假设，AIIAC功能障碍发生通过异常杆介导的信号与类似的技术，增强药理学工具和敲除小鼠品系。

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.