Inflammation mediated evolving changes in synapse structural integrity and dynamics in vivo in a mouse model of multiple sclerosis

多发性硬化症小鼠模型体内炎症介导的突触结构完整性和动态变化

• 批准号: 10176614
• 负责人: Rebecca Lynn Gillani
• 金额: $ 17.34万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10176614
• 关键词: Address; Affect; Animals; Architecture; Area; Atrophic; Autopsy; Award; Axon; Biometry; Brain; Chimeric Proteins; Chronic; Clinical; Communication; Communities; Complement; Demyelinations; Dendritic Spines; Development; Disease; Disease model; Excitatory Synapse; Experimental Autoimmune Encephalomyelitis; Experimental Models; Functional disorder; General Hospitals; Goals; Image; Imaging technology; Immune; Immunology; Impaired cognition; Individual; Inflammation; Inflammatory; Inhibitory Synapse; K-Series Research Career Programs; Label; Lead; Leadership; Lesion; Literature; Location; Massachusetts; Mediating; Mentors; Methodology; Methods; Modeling; Monitor; Multiple Sclerosis; Multiple Sclerosis Lesions; Mus; Myelin; Nerve Degeneration; Nerve Fibers; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neurologist; Neuronal Plasticity; Neurons; Outcome; Pathology; Pathway interactions; Physiological; Play; Population Heterogeneity; Postdoctoral Fellow; Pre-Clinical Model; Process; Proteins; Pyramidal Cells; Relapse; Research; Resolution; Rodent; Rodent Model; Role; Scaffolding Protein; Series; Shapes; Stroke; Structure; Symptoms; Synapses; Synaptic Receptors; Techniques; Technology; Testing; Time; Training; Trees; Visual Cortex; career development; cell motility; cellular imaging; density; disability; efficacy evaluation; experience; experimental study; fluorophore; gray matter; hippocampal pyramidal neuron; in vivo; in vivo imaging; in vivo two-photon imaging; innovation; interest; mouse model; multidisciplinary; multiple sclerosis patient; nervous system disorder; neuroimmunology; neuroinflammation; skills; therapeutic target; two-photon; white matter; young adult

This is an application for a K08 award for Dr. Rebecca Gillani, a neurologist at the Massachusetts General Hospital. She has rigorous prior training in neuroplasticity in rodent models of a neurodevelopmental disorder and stroke. In her initial post-doctoral experience, she has gained expertise in in vivo two-photon imaging technology working on a project to define basic principles of circuit wiring in the visual cortex. She now aims to take these state-of-the-art techniques for in vivo two-photon imaging of neurons and synapses and apply them to the study of neurodegeneration in rodent preclinical models of multiple sclerosis, her area of clinical interest. The goal of this career development award is to provide her the skills to make the transition from the study of physiologic circuit wiring and plasticity, to the independent study of disease models of neuroinflammation with training as follows: 1) Multi-disciplinary mentoring from experts in neurodegeneration, neuroimmunology, and in vivo two-photon imaging; 2) methodology for experimental autoimmune encephalomyelitis mouse model of multiple sclerosis; 3) didactic training in immunology and biostatistical methodology; and 4) communication and leadership career development. Her mentor Brian Bacskai is expert in in vivo two-photon imaging in neurodegenerative diseases, and her co-mentor Elly Nedivi is expert in in vivo two-photon imaging of neuron and synapse structure. Her advisors include experts in neurodegeneration, Rudolph Tanzi, and experts in neuroimmunology, Francisco Quintana and Staci Bilbo. While there is an immense literature and ongoing effort to define the immune mechanisms underlying multiple sclerosis pathology, a critical area of unmet need is defining the specific mechanisms of neuronal and synaptic dysfunction and degeneration during the course of multiple sclerosis. These neurodegenerative changes are a key determinant of disability in multiple sclerosis. It is likely that inflammation in early multiple sclerosis does not immediately lead to synapse loss. Instead there is more likely a series of evolving changes in synapse structural integrity and dynamics with the eventual outcome of synapse loss. In Aim 1, Dr. Gillani will leverage state-of-the- art in vivo two-photon imaging technologies for longitudinal monitoring of all the excitatory and inhibitory connections onto individual cortical pyramidal neurons in a living mouse in a model of multiple sclerosis. In Aim 2, Dr. Gillani will use new methods for reversible expansion and super-resolution imaging of cellular architecture to analyze for the presence of important synaptic proteins and inflammatory factors implicated in synaptic pathology in multiple sclerosis, by observing the same neurons and synapses imaged in live animals in Aim 1. The studies she proposes will provide a comprehensive picture of how diverse populations of synapses across the entire dendritic tree of cortical pyramidal cells undergo dynamic changes over 8 weeks in a mouse model of multiple sclerosis. This research will be the basis of a R01 application in year 4 of this proposed K08 award.

这是马萨诸塞州综合医院的神经科医生丽贝卡·吉拉尼（Rebecca Gillani）博士的K08奖。在神经发育障碍和中风的啮齿动物模型中，她对神经可塑性进行了严格的培训。在她最初的博士后经验中，她获得了在体内两光量成像技术方面的专业知识，该项目在一个项目中定义了视觉皮层中电路布线的基本原理。现在，她的目标是采用这些最先进的技术，用于对神经元和突触的体内两光子成像，并将其应用于多发性硬化症的啮齿动物临床前模型中的神经变性研究，这是她的临床感兴趣领域。该职业发展奖的目标是为她提供从生理电路接线和可塑性研究的过渡到对神经炎症的疾病模型的独立研究，并进行培训的独立研究：1）：1）来自神经变性，神经免疫学和In Vivo Trivo Tivivo Tivivo Tix Tixpyphoton Image的多学科指导； 2）多发性硬化症的实验性自身免疫性脑脊髓炎小鼠模型的方法； 3）免疫学和生物统计学方法的教学培训； 4）沟通和领导职业发展。她的导师Brian Bacskai是神经退行性疾病中体内双光子成像的专家，她的同事Elly Nedivi是神经元和突触结构的体内两光子成像的专家。她的顾问包括神经退行性的专家，鲁道夫·坦兹（Rudolph Tanzi）以及神经免疫学专家，弗朗西斯科·金塔纳（Francisco Quintana）和斯塔克·比尔博（Staci Bilbo）。尽管有巨大的文献和持续的努力来定义多发性硬化症病理学的免疫机制，但在多发性硬化症过程中，定义了未满足的重要需求的关键领域是确定神经元和突触功能障碍和变性的特定机制。这些神经退行性变化是多发性硬化症中残疾的关键决定因素。早期多发性硬化症的炎症可能不会立即导致突触丧失。取而代之的是，随着突触丧失的最终结果，突触结构完整性和动态的一系列不断变化的变化很可能发生。在AIM 1中，Gillani博士将利用体内两光子成像技术的最新技术来在多发性硬化症模型中对活着的小鼠中的所有兴奋性和抑制性连接进行纵向监测。在AIM 2中，吉拉尼博士将使用新方法来分析细胞体系结构的可逆扩展和超分辨率成像，以分析存在重要的突触蛋白和炎症因素和炎症因素与多发性硬化症中的突触病理相关的重要突触性因素，并通过观察相同的神经元和在现场的动物中产生的相同的神经元和突触。在多发性硬化症的小鼠模型中，皮质锥体细胞在8周内发生动态变化。这项研究将是该拟议K08奖的第4年R01申请的基础。