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: 8511659
• 负责人: Benjamin J Frankfort
• 金额: $ 18.3万
• 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/8511659
• 关键词: Adult; Affect; Amacrine Cells; Animal Model; Award; Basic Science; Behavior; Biological Assay; Blindness; Cancer Center Support Grant; Cell Count; Cell Death; Cell Survival; Cell physiology; Cells; Chairperson; Chemical Synapse; Clinical; Commit; Contrast Sensitivity; Data; Development; Diagnosis; Diagnostic; Disease; Doctor of Medicine; Doctor of Philosophy; Elderly; Electrical Synapse; Electrocoagulation; Electrodes; 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; 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学院医学科学家培训计划（MSTP）的成员，我的博士学位。论文的重点是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，还激发了我在约翰·霍普金斯（Johns Hopkins）威尔默眼科研究所（Wilmer Eye Institute）进行眼科居留，并在贝勒医学院（Baylor Medicine）的青光眼研究金。在培训期间，我一直坚定地致力于临床科学家的职业，并计划沿着这条道路继续。 我的直接专业目标是开发视网膜神经生理学领域的新基础研究技能，与我先前在遗传学和分子生物学方面的培训一起，可以用来更好地了解人类青光眼小鼠模型中发生的视网膜的基本变化。这项培训和研究将在我选择的导师Samuel M. Wu博士的密切监督下作为贝勒医学院眼科科科学系的终身教师。我得到了我们的董事长Dan B. Jones，医学博士的支持，他提供了实验室空间，财务支持以及对部门资源的全面访问，包括NEI Core for Vision Research。在提议的奖项期间，我将加强并扩大自己作为科学家的培训，将自己的遗传学专业知识与Wu博士的视网膜生理学知识合并，并成为一名独特而独立的研究者。我将开始一种临床眼科实践，重点介绍了青光眼的管理，将我的研究和临床兴趣联系起来。 我的长期专业目标是成为一个独立的研究者，其研究计划的重点是描述青光眼疾病的机制。我希望使用这些新信息来开发有见地的新翻译应用程序，以增强我们诊断和治疗青光眼的能力。 我的研究项目将集中于小鼠眼内压（IOP）升高的影响。初步数据表明，当IOP在小鼠中升高时，视网膜神经节细胞（RGC）和AII无链氨酸酯细胞（AIIACS）在观察到任何RGC结构变化之前都会减少光反应，并且由于异常杆介导的信号传导，可能会发生AIIAC干扰。观察到的视网膜细胞功能测定法的变化可能是青光眼中早期视觉障碍的基础。 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.我还将检验以下假设：辅助功能障碍通过使用类似技术的异常杆介导的信号传导发生，并用药理学工具和敲除小鼠菌株增强。