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

INTR升高小鼠模型中视网膜神经节细胞和无精细胞的功能

• 批准号: 8885832
• 负责人: Benjamin J Frankfort
• 金额: $ 13.1万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8885832
• 关键词: Adult; Affect; Amacrine Cells; Animal Model; Award; Basic Science; Behavior; Biological Assay; Blindness; Cell Count; Cell Death; Cell Survival; Cell physiology; Cells; Chairperson; Chemical Synapse; Clinical; Contrast Sensitivity; Core Grant; Data; Development; Diagnosis; Diagnostic; Disease; Doctor of Medicine; Doctor of Philosophy; Elderly; Electrical Synapse; Electrocoagulation; Event; Exhibits; Eye; Eye Development; Faculty; Fellowship; Financial Support; Functional disorder; Genetic; Glaucoma; Goals; Human; Institutes; Knockout Mice; Knowledge; Laboratories; Lasers; Life; Light; Link; Mediating; Medical; Medicine; Mentors; Microspheres; Modeling; Molecular Biology; Molecular Genetics; Monitor; Mouse Strains; Mus; Mutant Strains Mice; Neurodegenerative Disorders; Ophthalmology; Optic Nerve; Patients; Pattern; Phenotype; Physiologic Intraocular Pressure; Physiological; Physiology; Population; Publications; Publishing; Research; Research Personnel; Research Project Grants; Research Training; Residencies; Resources; Retina; Retinal; Retinal Ganglion Cells; Risk Factors; Sampling; Scientist; Signal Transduction; Slice; Staging; Supervision; Survival Rate; Synapses; System; Techniques; Testing; Time; TimeLine; Training; Training Programs; Vision; Vision research; Visual; Visual Acuity; career; college; ganglion cell; high intraocular pressure; human disease; improved; insight; interest; member; modifiable risk; mouse model; multi-electrode arrays; neurophysiology; optic nerve disorder; prevent; programs; research study; response; retinal neuron; retinal rods; skills; tool; visual performance; voltage clamp

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.

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。论文重点是眼睛发育的分子遗传学。这项研究发表了许多出版物和奖项，也激励我在约翰·霍普金斯大学威尔默眼科研究所进行眼科住院医师培训，并在贝勒医学院获得青光眼研究金。在我的培训期间，我仍然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走下去。 我当前的职业目标是开发一套新的视网膜神经生理学基础研究技能，再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人类青光眼小鼠模型中视网膜发生的根本变化。这项培训和研究将作为贝勒医学院眼科系的终身教授进行，并在我选择的导师 Samuel M. Wu 博士的密切监督下进行。我得到了我们的主席 Dan B. Jones 医学博士的支持，他为我提供了实验室空间、财务支持以及对部门资源的充分利用，包括 NEI 视觉研究核心拨款。在拟议的获奖期间，我将加强和扩展我作为科学家的培训，将我自己的遗传学专业知识与吴博士的视网膜生理学知识相结合，成为一名独特且独立的研究者。我将开始专注于青光眼治疗的临床眼科实践，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研究者，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富有洞察力的新转化应用，以增强我们诊断和治疗青光眼的能力。 我的研究项目将重点关注小鼠眼压 (IOP) 升高的影响。初步数据表明，当小鼠眼压升高时，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) 的光反应均已减弱，并且 AIIAC 干扰可能是由于视杆细胞介导的信号异常而发生的。这些视网膜细胞功能测定中观察到的变化可能是青光眼早期视觉障碍的基础。使用眼压升高的小鼠模型，我计划通过结合免疫组织化学技术、单细胞电压钳、允许同时对多个 RGC 采样的多电极阵列，建立 RGC 死亡、RGC 光反应和视觉功能的时间表。以及一个光电系统，可以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。我还将测试以下假设：AIIAC 功能障碍是通过使用类似技术的异常杆介导的信号传导而发生的，并通过药理学工具和基因敲除小鼠品系进行增强。