The impact of aneuploidy on neuronal cell behavior

非整倍体对神经细胞行为的影响

• 批准号: 9101062
• 负责人: RONG LI
• 金额: $ 20.25万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9101062
• 关键词: Affect; Aneuploidy; Behavior; Behavior Control; Behavioral; Bioinformatics; Biological Models; Brain; Brain Diseases; Cell Differentiation process; Cell Proliferation; Cell Survival; Cells; Chromosomes; Cognition; Complex; DNA copy number; Data; Development; Disease; Dissection; Experimental Models; Frequencies; Gene Expression; Generations; Genetic; Genetic Variation; Genome; Goals; Haploidy; Health; Hepatocyte; Human; In Vitro; Individual; Karyotype determination procedure; Knowledge; Lead; Learning; Light; Liver; Malignant Neoplasms; Mammalian Cell; Methods; Molecular; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Differentiation; Neurons; Organism; Pathogenesis; Pattern; Phenotype; Physiology; Play; Population; Process; Reporting; Role; Somatic Cell; Source; Stress; Stress Tests; Testing; Variant; Work; Yeasts; base; brain cell; cell behavior; cell fate specification; cell growth; cell motility; cell type; epigenetic regulation; in vivo; insight; nerve stem cell; neurodevelopment; neuron development; novel; research study; response; self-renewal; stem; stem cell population; stoichiometry; tool

DESCRIPTION (provided by applicant): Aneuploidy is the state of having an abnormal number of chromosomes in the genome. Although aneuploidy is often associated with diseases such as cancer and neural degeneration, recent studies have also demonstrated aneuploidy to be a large-effect mutation that could produce dramatic phenotypic variation and enable cells to rapidly adapt to environmental stress. Intriguingly, frequent aneuploidy has been reported to associate with certain normal somatic cells, such as liver hepatocytes and neurons and neural stem cells. The goal of this R21 study is to explore the idea that aneuploidy may be a genetic mechanism contributing to behavioral diversity of neurons. Specifically, we will use in vitro and ex vivo culture and differentiation of mouse neural stem cells (NSCs) as the experimental model to gain a first insight into how aneuploidy impacts the neuronal cell growth and differentiation and what might be the underlying mechanism. We will also investigate, in light of recent studies in unicellular organisms, whether neuronal aneuploidy may be induced by stress and/or provide phenotypic variation that enable evolutionary adaptation to stress conditions encountered by brain cells. Supporting the proposed experiments, we have developed an effective pipeline for the generation and isolation of aneuploid NSCs with homogeneous or heterogeneous karyotypes and established several methods for quantifying chromosome number and karyotyping of single or populations of cells. We have also established in our lab the methods for in vitro and ex vivo differentiation of NSCs. Our proposed study has the potential to shed light on the possible genetic mechanisms underlying neuronal complexity and the general impact of aneuploidy on the development and physiology of differentiated mammalian cells. The knowledge gained could advance the understanding of pathogenesis of brain disorders and other types of diseases due to chromosome numerical abnormalities.

描述（由申请人提供）：非整倍性是基因组中染色体数异常的状态。尽管非整倍性通常与癌症和神经变性等疾病有关，但最近的研究也证明了非整倍性是一种大效应突变，可以产生显着的表型变异，并使细胞能够快速适应环境应激。有趣的是，据报道，频繁的非整倍性与某些正常的体细胞相关，例如肝肝细胞，神经元和神经干细胞。这项R21研究的目的是探索以下观点：非整倍性可能是导致神经元行为多样性的遗传机制。具体而言，我们将使用小鼠神经干细胞（NSC）的体外和离体培养和分化作为实验模型，以首先深入了解非整倍性如何影响神经元细胞的生长和分化以及可能的基本机制。我们还将根据对单细胞生物的最新研究进行调查，是否可以通过压力诱导神经元非整倍性和/或提供表型变异，从而能够对脑细胞所遇到的应激状况的进化适应。在支持拟议的实验的支持下，我们开发了一种有效的管道，用于用均质或异质核型的非整倍体NSC生成和分离，并建立了几种方法来量化单个或种群的染色体数和核型。我们还在实验室中建立了NSC的体外和离体分化方法。我们提出的研究有可能阐明神经元复杂性的可能遗传机制以及非整倍性对分化哺乳动物细胞发育和生理学的一般影响。由于染色体数值异常，获得的知识可能会促进对脑疾病和其他类型疾病的发病机理的理解。