The effect of aneuploidy on cellular physiology and adaptation

非整倍性对细胞生理学和适应的影响

• 批准号: 8392874
• 负责人: RONG LI
• 金额: $ 39.64万
• 依托单位: STOWERS INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8392874
• 关键词: Affect; Alzheimer' s Disease; Aneuploid Cells; Aneuploidy; Animal Model; Antifungal Agents; Autistic Disorder; Cell Nucleus; Cell physiology; Cells; Cellular Stress; Cellular biology; Chemotherapy-Oncologic Procedure; Chromosomal Instability; Chromosomal Stability; Chromosomes; Collection; Congenital Abnormality; Copy Number Polymorphism; Development; Drug resistance; Epigenetic Process; Eukaryota; Eukaryotic Cell; Evolution; Exhibits; Experimental Models; Funding; Gene Dosage; Gene Expression; Gene Expression Profile; Gene Silencing; Genes; Genetic; Genome; Genome Stability; Genomics; Goals; Heterochromatin; Homeostasis; Investigation; Karyotype; Link; Malignant Neoplasms; Mediating; Methods; Mycoses; Pharmaceutical Preparations; Play; Population; Population Heterogeneity; Property; Proteins; Proteome; Public Health; Research; Role; Saccharomyces cerevisiae; Saccharomycetales; Stress; Testing; Variant; Work; Yeast Model System; Yeasts; base; cancer cell; fitness; genome-wide; histone modification; insight; response; stoichiometry; trend

DESCRIPTION (provided by applicant): Aneuploidy, the state of having uneven and abnormal chromosome copy numbers, is a frequently observed genome variation in eukaryotes and is a hallmark of cancer thought to play important roles in cancer evolution and development of drug resistance. The goal of this project is to use a creative combination of cell biology, genetics and genomic analyses in the model organism, the budding yeast Saccharomyces cerevisiae, to gain fundamental insights into how aneuploidy affects genome stability, cellular physiology and stress adaptation. We have recently developed several new methods to generate isogenic aneuploid yeast strains with random chromosome stoichiometry and to follow karyotype dynamics in aneuploid populations. These methods have allowed us to make important observations on the relationship between aneuploidy and cellular stress, and the profound impact of chromosome copy number variation on gene expression and fitness. The proposed study builds upon these findings with four specific aims. The first aim attempts to further understand the consequence of aneuploidy on gene expression by investigating its potential effects on epigenetic regulatory mechanisms. The second aim focuses on the question of why aneuploidy has a tendency to promote further chromosome instability leading to karyotypically mosaic populations adaptive to a wide range perturbation. The third aim investigates the possible existence of a common stress state associated with aneuploidy. The last aim explores a strategy of exploiting aneuploidy and karyotype dynamics, which may be potentially useful for treating cancer or fungal infections. PUBLIC HEALTH RELEVANCE: The proposed project is relevant to public health because aneuploidy, the state of having abnormal chromosome numbers, is a hallmark of cancer, is the cause of several congenital defects, and is linked to Alzheimer's disease and autism. However, the cause and consequence of aneuploidy remain poorly understood. The work proposed aims to gain fundamental insights into the impact of aneuploidy on gene expression and cellular physiology, and the relationship between aneuploidy and cellular stress. We also plan to explore a strategy of exploiting aneuploidy and karyotype dynamics, which may be potentially useful for treating cancer or fungal infections.

描述（由申请人提供）：非整倍性，即具有不均匀和异常的染色体拷贝数的状态，是真核生物中经常观察到的基因组变异，并且是癌症的标志，被认为在癌症进化和耐药性发展中发挥重要作用。该项目的目标是在模型生物（芽殖酵母酿酒酵母）中创造性地结合细胞生物学、遗传学和基因组分析，以获得非整倍性如何影响基因组稳定性、细胞生理学和应激适应的基本见解。我们最近开发了几种新方法来生成具有随机染色体化学计量的等基因非整倍体酵母菌株，并跟踪非整倍体群体的核型动态。这些方法使我们能够对非整倍性和细胞应激之间的关系以及染色体拷贝数变异对基因表达和适应性的深远影响进行重要观察。拟议的研究以这些发现为基础，有四个具体目标。第一个目标试图通过研究非整倍性对表观遗传调控机制的潜在影响来进一步了解非整倍性对基因表达的影响。第二个目标集中于以下问题：为什么非整倍性有进一步促进染色体不稳定性的趋势，从而导致核型嵌合群体适应大范围的扰动。第三个目标是研究与非整倍性相关的常见应激状态的可能存在。最后一个目标探索利用非整倍性和核型动态的策略，这可能对治疗癌症或真菌感染有用。 公共健康相关性：拟议的项目与公共健康相关，因为非整倍性（染色体数量异常的状态）是癌症的标志，是多种先天性缺陷的原因，并且与阿尔茨海默病和自闭症有关。然而，非整倍体的原因和后果仍然知之甚少。拟议的工作旨在深入了解非整倍性对基因表达和细胞生理学的影响，以及非整倍性与细胞应激之间的关系。我们还计划探索一种利用非整倍性和核型动态的策略，这可能对治疗癌症或真菌感染有用。