Exploiting principles of timing-dependent synaptic plasticity to treat amblyopia

利用时间依赖性突触可塑性原理治疗弱视

• 批准号: 10454342
• 负责人: Eric Dean Gaier
• 金额: $ 23.93万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10454342
• 关键词: Adolescent; Advisory Committees; Age; Amblyopia; Animal Model; Animals; Area; Biological Markers; Boston; Brain; Calcium; Chemosensitization; Child; Childhood; Complex; Contralateral; Data; Dependence; Development; Ear; Electrophysiology (science); Environment; Evoked Potentials; Exhibits; Eye; Fellowship; Foundations; Functional disorder; Future; Goals; Head; Image; Imaging Techniques; In Vitro; Institutes; Ipsilateral; Laboratories; Learning; Massachusetts; Mediating; Mentors; Mentorship; Modeling; Mus; N-Methyl-D-Aspartate Receptors; NGFRAP1 gene; NMDA receptor A1; Neuronal Plasticity; Neurons; Ocular Dominance; Ocular Physiology; Ophthalmology; Patients; Pediatric Hospitals; Phase; Physiology; Play; Population; Productivity; Program Development; Property; Recovery; Research; Residencies; Resolution; Resources; Role; Scientist; Signal Transduction; Stimulus; Synapses; Synaptic plasticity; Techniques; Technology; Testing; Therapeutic; Time; Training; Training Programs; Universities; Ursidae Family; V1 neuron; Vision Disorders; Visual; Visual Cortex; Visual Pathways; Visual system structure; Work; area striata; awake; career; career development; design; experience; experimental study; improved; insight; medical schools; monocular; monocular deprivation; mouse model; movie; neurophysiology; novel; novel strategies; novel therapeutic intervention; novel therapeutics; programs; receptor expression; research and development; response; two-photon; visual dysfunction; visual information; visual plasticity; visual process; visual stimulus

This proposal describes a 5-year training program for the development of an academic career focused on improving therapy for amblyopia by advancing our understanding and exploitation of synaptic plasticity mechanisms. My graduate training in electrophysiology and synaptic plasticity carried through during my ophthalmology residency and neuro-ophthalmology fellowship at Massachusetts Eye and Ear Infirmary (MEEI) and Harvard Medical School (HMS). During this time, I have been working in the laboratory of Dr. Mark Bear at the nearby Massachusetts Institute of Technology (MIT) gathering early data on a potential new therapeutic approach for amblyopia. This work will continue during my pediatric ophthalmology fellowship at Boston Children’s Hospital (BCH) through July 2019. I wish to continue this research and my development to prepare for an independent research career. My long-term goals include making major contributions to the understanding of the synaptic mechanisms underlying amblyopia while providing translational insights that can yield new therapeutic approaches for patients with central visual dysfunction. Dr. Bear, a world expert on amblyopia and synaptic physiology and plasticity with a proven track record of productivity and mentorship, will serve as mentor. An advisory committee comprised of Drs. David Hunter (BCH/HMS), Ed Boyden (MIT), and Peter Bex (Northeastern University) will guide my research and career development. This MEEI-sponsored project will take place in the rich environments of MIT, with access to resources at MEEI, BCH and HMS. The proposed research program examines interocular temporal phase offset training (TPOT), which is predicated on timing-dependent principles of synaptic plasticity, as a potential new therapeutic approach to amblyopia while elucidating properties of signal integration in visual cortex. In our initial experiments, we show that TPOT is sufficient to selectively strengthen visually evoked potentials in the inherently weaker ipsilateral eye and shift ocular dominance in mice. In the first Aim, I will characterize the properties of TPOT, including stimulus selectivity, optimal parameters for efficacy and age limits. I will define the interaction of signal phase with contrast reduction, which has been used to treat amblyopia, and determine the cortical laminar-specific effects of TPOT. The second Aim is to gain mechanistic insights into the TPOT effect. I will learn and apply 2- photon calcium imaging techniques to define the ocular dominance shift at the neuronal level, and selectively target NMDA receptor expression in the visual cortex to uncover their role in TPOT-induced visual cortical plasticity. The third Aim will apply TPOT to monocularly deprived mice, a widely studied animal model for amblyopia, with the goals of promoting visual recovery and generalizing the TPOT effect. In conducting these experiments, I will gain considerable experience with advanced techniques to study murine visual physiology in the context of amblyopia, thereby providing me with crucial technical, conceptual and professional foundations to build my early career as an independent clinician-scientist and future contributor and expert to the field.

该提案描述了一项为期5年的培训计划，以开发以学术职业为重点 通过促进我们对突触可塑性的理解和开发来改善弱视治疗 机制。我在我的电生理学和合成可塑性方面进行的研究生培训。 马萨诸塞州眼科和耳科医院（MEEI）的眼科住宅和神经浏览型研究金 和哈佛医学院（HMS）。在这段时间里，我一直在马克·贝尔博士的实验室工作 附近的马萨诸塞州理工学院（MIT）收集有关潜在新疗法的早期数据 弱视的方法。这项工作将在我在波士顿的小儿眼科奖学金期间继续 儿童医院（BCH）至2019年7月。我希望继续这项研究和我的发展以准备 从事独立的研究职业。我的长期目标包括为 了解弱视潜在的合成机制，同时提供可以转化的见解 为中央视觉功能障碍患者提供新的治疗方法。 Bear博士，世界专家 弱视和突触生理学和可塑性具有可靠的生产力和心态记录，将 担任导师。咨询委员会完成了博士。 David Hunter（BCH/HMS），Ed Boyden（麻省理工学院）和 彼得·贝克斯（Peter Bex）（东北大学）将指导我的研究和职业发展。这是由Meei赞助的 项目将在MIT的丰富环境中进行，并在MEEI，BCH和HMS上访问资源。 拟议的研究计划研究了眼内时间相位偏移训练（TPOT），这是 以突触可塑性的时间依赖性原理为基础，是一种潜在的新疗法 弱视的同时阐明视觉皮层中信号积分的特性。在最初的实验中，我们显示 该TPOT足以在遗传较弱的同侧选择性地有选择性地强大的视觉唤起电位 小鼠的眼睛和移动眼优势。在第一个目标中，我将表征TPOT的属性，包括 刺激选择性，效率和年龄限制的最佳参数。我将定义信号阶段的相互作用 降低对比度，该对比度已用于治疗弱视，并确定皮质层状特异性 TPOT的影响。第二个目的是获得对TPOT效应的机械见解。我将学习并应用2- 光子钙成像技术以定义眼部占主导地位在神经元水平上，并有选择地 靶NMDA受体在视觉皮层中的表达，以发现其在TPOT诱导的视觉皮质中的作用 可塑性。第三个目标将把TPOT应用于单眼被剥夺的小鼠，这是一种广泛的研究菌动物模型 弱视，其目标是促进视觉恢复并推广TPOT效应。在执行这些方面 实验，我将获得有关先进技术的考虑经验，以研究鼠类视觉生理学 弱视的背景，从而为我提供了至关重要的技术，概念和专业基础 为了建立我作为独立临床科学家和未来贡献者和该领域的专家的早期职业。