Gene regulatory mechanisms that assign and maintain motor neuron terminal differe

分配和维持运动神经元末梢的基因调控机制不同

• 批准号: 8737986
• 负责人: Paschalis Kratsios
• 金额: $ 9万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-20 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8737986
• 关键词: Acetylcholine; Ache; Adult; Advisory Committees; Amyotrophic Lateral Sclerosis; Bioinformatics; Biological Assay; Biological Models; Caenorhabditis elegans; Candidate Disease Gene; Chordata; Collaborations; Defect; Development; Development Plans; Diagnosis; Differentiation Antigens; Disease; Enhancers; Ensure; Etiology; Family; Family member; Fibrinogen; Foundations; Funding; Future; Gene Targeting; Genes; Genetic; Goals; Human; Human Pathology; Ion Channel; K-Series Research Career Programs; Knowledge; Laboratories; Life; Mentors; Microarray Analysis; Molecular; Molecular Profiling; Motor Neurons; Mus; Mutagenesis; Mutant Strains Mice; Nematoda; Neurobiology; Neurotransmitter Receptor; Orthologous Gene; Pathway interactions; Phase; Phylogeny; Positioning Attribute; Property; Proteins; Regulator Genes; Research; Research Personnel; Role; Spinal; Spinal Cord; Spinal Muscular Atrophy; Spinal cord injury; Testing; Time Management; Training; Universities; Vertebrates; Work; base; career development; chromatin immunoprecipitation; effective therapy; embryonic stem cell; genome sequencing; genome-wide; in vivo; insight; member; motor neuron development; motor neuron function; mouse genome; novel; public health relevance; receptor; screening; skills; success; tool; transcription factor

DESCRIPTION (provided by candidate): "Gene regulatory mechanisms that assign and maintain motor neuron terminal differentiation" Summary: Defects in motor neuron (MN) function or survival result in severe human conditions such as amyotrophic lateral sclerosis (ALS), and spinal muscular atrophy (SMA). There are no effective treatments for MN disorders in part due to our poor understanding of the last steps of MN development, i.e., the induction of MN terminal differentiation genes. In addition, the molecular mechanisms that maintain the expression of MN terminal differentiation genes during adult life (and thereby ensure MN function) are largely unknown. We have recently provided the first insights on the regulatory mechanisms that establish MN terminal differentiation during development and maintain it in adult life. Using a nematode and a simple chordate as model systems, we showed that the COE (Collier, Olf, Ebf) family of transcription factors assigns and maintains MN terminal differentiation. In this Career Development Proposal, C In Aim #1, I will test the hypothesis that Ebf2 (COE family member) is required for terminal differentiation of spinal MNs using my expertise in conditional mouse mutagenesis. The goal of Aim #2 is to identify novel MN terminal differentiation markers in vertebrates using ChIP-sequencing and microarray technology on mouse embryonic stem cell (mESC)-derived MNs. This is a much-anticipated goal in the MN field as currently only the acetylcholine (ACh) pathway genes serve as bona fide markers of MN terminal differentiation. In Aim #3, I will aim to reveal other evolutionarily conserved transcripton factors that are required for terminal differentiation of specific MN subtypes in C. Elegans. The knowledge gained from these aims will lend to our understanding of how MN terminal differentiation is established during development and maintained throughout life, and may provide novel entry points into the etiology, diagnosis or treatment of MN disorders. If funded, this Career development Award (CDA) would afford me the opportunity to expand my background in C. Elegans genetics, develop additional expertise in vertebrate neurobiology, obtain the necessary training in ChIP-sequencing and the use of bioinformatic tools; skills critical for my future success as an independent researcher. Formal and informal interactions with my Advisory Committee will assess my progress on the proposed Aims and provide advice. Finally, professional skills (e.g. mentoring, research presentation, time management) vital to my long-term success as an academic will be gained during the K99 phase through Columbia University courses and advice by my advisory committee and my mentor. Together, the proposed studies and career development plan will ensure I achieve my long-term goal; to establish a successful laboratory at a major University and make significant contributions to the MN field.

描述（由候选人提供）：“分配和维持运动神经元终末分化的基因调控机制”摘要：运动神经元（MN）功能或存活缺陷导致严重的人类疾病，如肌萎缩性侧索硬化症（ALS）和脊髓性肌萎缩症（SMA）。对于MN疾病没有有效的治疗方法，部分原因是我们对MN发展的最后步骤缺乏了解，即，MN终末分化基因的诱导。此外，在成年期维持MN终末分化基因表达（从而确保MN功能）的分子机制在很大程度上是未知的。 我们最近提供了关于在发育过程中建立MN末端分化并在成年生活中维持它的调节机制的第一个见解。使用线虫和一个简单的脊索动物作为模型系统，我们表明，COE（Collier，Olf，Ebf）家族的转录因子分配和维持MN终端分化。在这份职业发展计划中，我将利用我在条件性小鼠诱变方面的专业知识，检验Ebf 2（COE家族成员）是脊髓MN终末分化所必需的假设。目标#2的目标是使用ChIP测序和微阵列技术在小鼠胚胎干细胞（mESC）衍生的MN上鉴定脊椎动物中的新MN末端分化标记物。这是MN领域备受期待的目标，因为目前只有乙酰胆碱（ACh）途径基因作为MN终末分化的真正标志物。在目标#3中，我将致力于揭示其他进化上保守的转录因子，它们是C.优雅。从这些目标中获得的知识将有助于我们了解MN终末分化是如何在发育过程中建立并在整个生命过程中维持的，并可能为MN疾病的病因学，诊断或治疗提供新的切入点。 如果得到资助，这个职业发展奖（CDA）将为我提供一个机会，扩大我在C语言方面的背景。Elegans遗传学，发展脊椎动物神经生物学方面的额外专业知识，获得ChIP测序和生物信息学工具使用方面的必要培训;这些技能对我未来作为独立研究人员的成功至关重要。与我的咨询委员会的正式和非正式互动将评估我在拟议目标方面的进展，并提供建议。最后，专业技能（如指导，研究报告，时间管理）至关重要，我的长期成功作为一个学术将获得在K99阶段通过哥伦比亚大学的课程和建议，我的顾问委员会和我的导师。总之，拟议的研究和职业发展计划将确保我实现我的长期目标;在一所主要大学建立一个成功的实验室，并为MN领域做出重大贡献。