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Genetic labeling and visualization of CSMN in models of motor neuron disorders

运动神经元疾病模型中 CSMN 的基因标记和可视化

基本信息

批准号：
8731290
负责人：
Pembe Hande Ozdinler
金额：
$ 19.12万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-15 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8731290
关键词：
ARHGEF5 gene Affect Amyotrophic Lateral Sclerosis Anatomy Attention Biology Brain CCL1 gene Cellular Structures Cellular biology Cerebral cortex Cessation of life Complex Corticospinal Tracts Crossbreeding Defect Development Disease EP300 gene Frontotemporal Dementia Frustration Generations Genes Genetic Goals Grant Health Hereditary Spastic Paraplegia Human Human Pathology Imagery Knockout Mice Label Lead Life Mediating Mind Modeling Molecular Molecular Genetics Molecular Profiling Motor Motor Cortex Motor Neuron Disease Motor Neurons Movement Movement Disorders Mus Mutation Neurodegenerative Disorders Neurons Operative Surgical Procedures Pathology Patients Persons Population Primary Lateral Sclerosis Reporter Signal Transduction Source Spinal Cord Staging Structure System Time Transgenic Organisms Translating UCHL1 gene Visual base effective therapy hippocampal pyramidal neuron human TFRC protein improved in vivo molecular marker motor neuron degeneration motor neuron function mouse model novel promoter protein TDP-43 public health relevance ranpirnase success tool treatment strategy tyrosine kinase ABL1

项目摘要

DESCRIPTION (provided by applicant): There are thousands of different neuron populations in our cerebral cortex, but in neurodegenerative diseases only a select neuron population show primary vulnerability and undergo progressive degeneration. Corticospinal motor neurons (CSMN) are large pyramidal neurons that are located in layer V of the motor cortex. Their cellular structure is very unique and they function as the "spokes person"of the cerebral cortex for the initiation and modulation of movement. Voluntary movement is the act of a clever and well-informed mind. Therefore CSMN receive information from numerous neurons, including long-distance projection and local circuitry neurons. CSMN's unique ability to integrate and translate this information into one signal towards spinal cord targets sets it apart from other cortical neurons. Therefore its degeneration has severe consequences that lead to various movement disorders. There is a developing need to understand the basis of CSMN degeneration in diseases. However, identification and visualization of CSMN is not easy as they are embedded among thousands of other neuron populations within the cerebral cortex. We recently generated a novel reporter line, the UCHL1-eGFP mice, in which CSMN are genetically labeled in the motor cortex. eGFP expression under the control of UCHL1 promoter is stable, persistent up to P800 in vivo, and is restricted to CSMN in the motor cortex. CSMN identity of eGFP+ neurons in the motor cortex are identified by anatomy, retrograde labeling, molecular marker expression profile and electrophysiological analysis. This reporter line offers many unique advantages; a) we can for the first time visualize CSMN without any need for a retrograde labeling surgery; b) CSMN can be purified by FACS- mediated approaches at different stages in life; c) the cellular and molecular mechanisms that are responsible for CSMN vulnerability and degeneration can be studied in detail and with precision; d) most importantly this novel reporter line can be crossed to various mouse models of movement disorders to investigate the biology of CSMN with respect to disease. In this proposal, our goal is to bring visual clarity to CSMN in various mouse models of motor neuron diseases. We will be crossing UCHL1-eGFP mice with the recently identified mouse models that show potential involvement of upper motor neuron degeneration in disease pathology. Due to time limitations of R21 grant, we will characterize the timing and extent of CSMN degeneration in a limited number of mouse models, such as the Tdp43A315T and Alsin KO mice. The tools we generate and the approach we develop will help generation and characterization of other reporter mouse models, and will improve our efforts of understanding the cellular and molecular mechanisms behind CSMN vulnerability and degeneration.

描述（由申请人提供）：在我们的大脑皮层中有数千种不同的神经元群，但在神经退行性疾病中，只有选定的神经元群表现出原发性易感性并经历进行性变性。皮质脊髓运动神经元（CSMN）是位于运动皮层第五层的大型锥体神经元。它们的细胞结构非常独特，它们是大脑皮层的“代言人”，负责发起和调节运动。自发的运动是聪明和见多识广的头脑的行为。因此，CSMN接收来自多个神经元的信息，包括远距离投射神经元和局部回路神经元。CSMN将这些信息整合并转化为一个针对脊髓目标的信号的独特能力使其与其他皮质神经元区别开来。因此，它的退化有严重的后果，导致各种运动障碍。有一个发展的需要，了解疾病的CSMN变性的基础。然而，CSMN的识别和可视化并不容易，因为它们嵌入在大脑皮层内成千上万的其他神经元群中。我们最近产生了一个新的报告系，UCHL1-eGFP小鼠，其中CSMN在运动皮质中被遗传标记。在UCHL1启动子控制下，eGFP在体内的表达稳定，持续到P800，且仅限于运动皮层的CSMN。通过解剖、逆行标记、分子标记表达谱和电生理分析确定运动皮层eGFP+神经元的CSMN身份。这条记者专线提供了许多独特的优势；a)我们首次可以可视化CSMN，而不需要逆行标记手术；b) CSMN可以在生命的不同阶段通过FACS介导的方法纯化；c)可以详细和精确地研究导致CSMN脆弱性和退化的细胞和分子机制；d)最重要的是，这种新的报告线可以交叉到各种运动障碍的小鼠模型中，以研究CSMN与疾病的生物学关系。在本提案中，我们的目标是使CSMN在各种运动神经元疾病小鼠模型中的视觉清晰度。我们将把UCHL1-eGFP小鼠与最近鉴定的显示上运动神经元退化在疾病病理中潜在参与的小鼠模型杂交。由于R21拨款的时间限制，我们将在有限数量的小鼠模型（如Tdp43A315T和Alsin KO小鼠）中表征CSMN退化的时间和程度。我们生成的工具和我们开发的方法将有助于生成和表征其他报告小鼠模型，并将提高我们对CSMN脆弱性和退化背后的细胞和分子机制的理解。