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: 10674755
• 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/10674755
• 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; Exhibits; Eye; Fellowship; Foundations; Functional disorder; Future; Goals; Head; Image; Imaging Techniques; In Vitro; 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; V1 neuron; Vision Disorders; Visual; Visual Cortex; Visual Pathways; Visual System; Visual evoked cortical potential; Work; area striata; awake; career; career development; design; efficacy evaluation; experience; experimental study; improved; insight; medical schools; monocular; monocular deprivation; mouse model; movie; neurophysiology; novel; novel strategies; novel therapeutic intervention; novel therapeutics; postsynaptic; postsynaptic neurons; presynaptic; 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.

该提案描述了一个为期5年的培训计划，以发展学术生涯为重点， 通过提高我们对突触可塑性的理解和利用来改善弱视的治疗 机制等我的研究生训练在电生理学和突触可塑性进行了通过在我的 马萨诸塞州眼耳医院眼科住院医师和神经眼科奖学金 和哈佛医学院（HMS）。在此期间，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）收集了一种潜在的新疗法的早期数据， 弱视的治疗方法这项工作将继续在我的儿科眼科奖学金在波士顿举行 儿童医院（BCH）至2019年7月。我希望继续这项研究和我的发展， 从事独立的研究工作。我的长期目标包括为 了解弱视的突触机制，同时提供翻译的见解， 为中枢性视觉功能障碍患者提供新的治疗方法。熊博士，一位世界级的 弱视和突触生理学和可塑性与生产力和指导的良好记录，将 担任导师。由大卫亨特博士（BCH/HMS）、艾德博伊登博士（MIT）和 Peter Bex（东北大学）将指导我的研究和职业发展。这个MEEI赞助的 项目将在麻省理工学院的丰富环境中进行，可以访问MEEI，BCH和HMS的资源。 拟议的研究计划检查眼间时间相位偏移训练（TPOT），这是 基于突触可塑性的时间依赖性原则，作为一种潜在的新的治疗方法， 弱视，同时阐明视觉皮层信号整合的特性。在我们最初的实验中，我们发现 TPOT足以选择性地加强固有较弱同侧的视觉诱发电位， 眼睛并改变小鼠的眼睛优势。在第一个目标中，我将描述TPOT的性质，包括 刺激选择性、功效的最佳参数和年龄限制。我将定义信号相位的相互作用 与对比度降低，这已被用来治疗弱视，并确定皮质层特异性 TPOT的影响第二个目标是获得TPOT效应的机理见解。我将学习和应用2- 光子钙成像技术在神经元水平上确定眼优势移位， 目的研究NMDA受体在视皮层的表达，揭示其在TPOT诱导的视皮层神经元损伤中的作用。 可塑性第三个目标是将TPOT应用于单眼剥夺小鼠，这是一种广泛研究的动物模型， 弱视，目的是促进视力恢复和推广TPOT效果。在进行这些 通过实验，我将获得大量使用先进技术研究小鼠视觉生理学的经验， 弱视的背景，从而为我提供了关键的技术，概念和专业基础 建立我的早期职业生涯作为一个独立的临床科学家和未来的贡献者和专家的领域。

项目成果

Comments on: Partial Recovery of Amblyopia After Fellow Eye Ischemic Optic Neuropathy: Response.

评论：同眼缺血性视神经病变后弱视部分恢复：反应。

• DOI: 10.1097/wno.0000000000001996
• 发表时间: 2024
• 期刊: Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society
• 作者: Gaier,EricD;Bear,MarkF
• 通讯作者: Bear,MarkF

Ptosis as Clinical Presentation in a Patient With Emery-Dreifuss Muscular Dystrophy Type 5.

• DOI: 10.1097/wno.0000000000001187
• 发表时间: 2021-09-01
• 期刊: Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society
• 作者: Douglas KAA;Douglas VP;Gaier ED;Chwalisz BK
• 通讯作者: Chwalisz BK

Peripapillary Choroidal Vascularity and Visual Correlates in Non-Arteritic Anterior Ischemic Optic Neuropathy Using Swept-Source Optical Coherence Tomography.

使用扫描源光学相干断层扫描研究非动脉炎性前部缺血性视神经病变的视乳头周围脉络膜血管和视觉相关性。

• DOI: 10.3389/fopht.2022.848040
• 发表时间: 2022
• 期刊: Frontiers in ophthalmology
• 作者: Lu,EdwardS;Katz,Raviv;Miller,JohnB;Gaier,EricD
• 通讯作者: Gaier,EricD

Absent Foveal Avascular Zone in Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay.

• DOI: 10.1097/wno.0000000000001050
• 发表时间: 2021-06-01
• 期刊: Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society
• 作者: Douglas VP;Douglas KAA;Miller JB;Gaier ED
• 通讯作者: Gaier ED

Cauterization-mediated restriction from penetrating orbital trauma.

烧灼介导的穿透性眼眶创伤的限制。

• DOI: 10.1016/j.jaapos.2023.11.008
• 发表时间: 2024
• 期刊: Journal of AAPOS : the official publication of the American Association for Pediatric Ophthalmology and Strabismus
• 作者: Liebman,DanielL;Weinert,MargueriteC;Dohlman,JennyC;Hennein,Lauren;Gaier,EricD
• 通讯作者: Gaier,EricD