Defining an Electrophysiological Phenotype of ALS Patient-Derived Motor Neurons

定义 ALS 患者来源的运动神经元的电生理表型

• 批准号: 8827864
• 负责人: Brian Jason Wainger
• 金额: $ 19.35万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8827864
• 关键词: Adult; Advisory Committees; Affect; Amyotrophic Lateral Sclerosis; Antiepileptic Agents; Biological; Biology; Biometry; Boston; Brain; C9ORF72; Cell Line; Cells; Cessation of life; Clinic; Coculture Techniques; Collaborations; Data; Disease; Disease Marker; Disease Progression; Electrophysiology (science); Exhibits; Exposure to; Faculty; Familial Amyotrophic Lateral Sclerosis; Five-Year Plans; Gene Mutation; General Hospitals; Genetic Transcription; Glutamates; Health; Human; In Vitro; Individual; Inherited; Institutes; K-Series Research Career Programs; Lead; Massachusetts; Measures; Mentors; Methods; Modeling; Molecular Biology; Molecular Profiling; Morphology; Motor; Motor Neurons; Mus; Muscle Contraction; Mutation; Nerve Degeneration; Neural Conduction; Neurobiology; Neurodegenerative Disorders; Neuroglia; Neurologist; Neurology; Neuromuscular Junction; Neurons; Neurosciences; Patients; Pediatric Hospitals; Pharmaceutical Preparations; Pharmacology; Phenotype; Physician Executives; Play; Positioning Attribute; Potassium; Potassium Channel; Process; Property; Relative (related person); Research; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Role; Scientist; Senior Scientist; Signal Transduction; Sodium; Spinal Cord; Stem cells; System; Techniques; Testing; Tetrodotoxin; Therapeutic; Training Programs; Training Support; Variant; Work; base; bean; career; disease-causing mutation; electrical property; excitotoxicity; experience; extracellular; gene correction; human data; human stem cells; improved; indexing; induced pluripotent stem cell; insight; lentiviral-mediated; medical schools; molecular marker; multi-electrode arrays; nervous system disorder; novel strategies; patch clamp; professor; programs; regenerative; skills; stem cell biology; stem cell technology; superoxide dismutase 1; translational medicine; trial design; uptake; voltage

DESCRIPTION (provided by applicant): This proposal describes a five-year plan for Brian Wainger to achieve independence as an investigator who uses patient-derived motor neurons to study amyotrophic lateral sclerosis (ALS). The candidate is a neurologist at Massachusetts General Hospital. He has a strong research background in electrophysiology and molecular biology, as well as recent successful experience recording from patient-derived motor neurons, a technique that he will apply to the proposed project. Dr. Clifford Woolf, the primary mentor, is Professor of Neurology and Neurobiology at Harvard Medical School and Director of the Neurobiology Program at Children's Hospital Boston. He is a world expert in neuroscience, and has supervised numerous trainees who now hold academic faculty positions. Dr. Kevin Eggan, the co- mentor, is an HHMI Early Career Scientist and Professor in the Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute. He is a leader in the stem cell field and in ALS research. An advisory committee of senior scientists able to provide additional expert guidance includes also Dr. Merit Cudkowicz and Dr. Bruce Bean. The research will be performed at Children's Hospital. ALS is a devastating, untreatable neurological disease characterized by progressive weakness and death of neurons in the motor system. Most cases are sporadic, but about 10% are familial. The primary function of a motor neuron is to collect and integrate signals from the brain and spinal cord and transmit an outgoing electrical signal that results in muscle contraction. The researchers hypothesize that investigating the electrical properties of healthy and diseased motor neurons will help increase understanding of ALS and yield insight into how to treat the disease. Using recent advances in stem-cell technology, the investigators have derived motor neurons from ALS and control subjects and found that motor neurons derived from patients with familial ALS are hyperexcitable, meaning that they are prone to too much activity, and that the hyperexcitability may contribute to motor neuron death in ALS. The proposed project consists of evaluating hyperexcitability and motor neuron death in a range of inherited and sporadic variants of ALS. The project will yield a mechanistic understanding and characterization of the observed hypexcitability, specifically with regard to the role of voltage-gated potassium ion channels. Through the training program, the investigator will acquire critical expertise using techniques in stem cell biology and single cell RNA expression analysis, as well as didactic exposure to key components of translational medicine such as biostatistics and trial design. With these skills, the applicant will successfully complete the proposed project and transition to independence, where he can exploit this novel approach of modeling human neurological disease using human neurons more broadly.

描述（由申请人提供）：本提案描述了Brian Wainger作为使用患者源性运动神经元研究肌萎缩侧索硬化症（ALS）的研究者实现独立的五年计划。候选人是马萨诸塞州总医院的神经科医生。他在电生理学和分子生物学方面有很强的研究背景，最近还成功地记录了来自患者的运动神经元的经验，他将把这项技术应用于拟议的项目。克利福德·伍尔夫博士是哈佛医学院的神经病学和神经生物学教授，也是波士顿儿童医院神经生物学项目的主任。他是神经科学领域的世界级专家，曾指导过许多现在担任学术教职的学员。共同导师凯文·埃根博士是HHMI早期职业科学家，也是干细胞和再生生物学系以及哈佛干细胞研究所的教授。他是干细胞领域和ALS研究的领导者。能够提供额外专家指导的资深科学家咨询委员会还包括Merit Cudkowicz博士和布鲁斯比恩博士。这项研究将在儿童医院进行。ALS是一种毁灭性的、无法治愈的神经系统疾病，其特征是运动系统中的神经元进行性虚弱和死亡。大多数病例是散发性的，但约10%是家族性的。运动神经元的主要功能是收集和整合来自大脑和脊髓的信号，并传输导致肌肉收缩的传出电信号。研究人员假设，研究健康和患病运动神经元的电特性将有助于增加对ALS的理解，并深入了解如何治疗这种疾病。利用干细胞技术的最新进展，研究人员从ALS和对照受试者中获得了运动神经元，并发现来自家族性ALS患者的运动神经元是过度兴奋的，这意味着它们易于过度活动，并且过度兴奋可能导致ALS中的运动神经元死亡。拟议的项目包括评估一系列遗传性和散发性ALS变体中的过度兴奋和运动神经元死亡。该项目将产生观察到的hyperexcitability的机制的理解和表征，特别是关于电压门控钾离子通道的作用。通过培训计划，研究者将获得关键的专业知识，使用干细胞生物学和单细胞RNA表达分析技术，以及教学接触转化医学的关键组成部分，如生物统计学和试验设计。凭借这些技能，申请人将成功完成拟议的项目并过渡到独立，在那里他可以更广泛地利用这种使用人类神经元建模人类神经疾病的新方法。