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

基本信息

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
项目类别：
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&apos 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

项目摘要

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）：非整倍性是具有不均匀和异常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起着重要作用。该项目的目的是在模型生物体中使用细胞生物学，遗传学和基因组分析的创造性组合，即萌芽的酵母菌酿酒酵母，从而获得了针对基因组稳定性，细胞生理学，细胞生理和压力适应的基本见解。我们最近开发了几种新方法，以生成具有随机染色体化学计量的等源性非源性酵母菌菌株，并遵循非整倍体群体的核型动力学。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化对基因表达和适应性的深刻影响进行重要观察。拟议的研究以四个特定目标为基础。第一个目标试图通过研究其对表观遗传调节机制的潜在影响，以进一步了解基因表达的后果。第二个目标的重点是为什么非整倍性倾向于促进进一步的染色体不稳定性，从而导致核型马赛克种群适应广泛的扰动。第三目调查了与非整倍性相关的共同应力状态的可能存在。最后一个目标探讨了开发非整倍性和核型动力学的策略，这可能对于治疗癌症或真菌感染可能有用。公共卫生相关性：拟议的项目与公共卫生有关，因为非整倍性（具有异常的染色体数量）是癌症的标志，是几种先天性缺陷的原因，与阿尔茨海默氏病和自闭症有关。但是，非整倍性的原因和后果仍然很少理解。该作品旨在获得对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的基本见解。我们还计划探索一种开发非整倍性和核型动力学的策略，这可能对治疗癌症或真菌感染有可能有用。