IDENTIFICATION OF MECHANISMS OF CHROMOSOMAL ABERRATIONS (FUNCTIONAL CYTOGENETICS)

染色体畸变机制的鉴定（功能细胞遗传学）

• 批准号: 6290868
• 负责人: Thomas E. Ried
• 金额: --
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6290868
• 关键词: carcinogenesis; chromosome aberrations; chromosome translocation; cytogenetics; karyotype; neoplasm /cancer genetics

The analysis of a large number of human and mouse solid tumors has established the relevance of genomic imbalances as the premier genetic aberration in cancers of epithelial origin. 95% of all aberrations result in copy number changes reflecting gains and losses of specific chromosomes, chromosome arms and chromosomal regions. Therefore, solid tumors differ in their cytogenetic aberration pattern from hematological malignancies, that are characterized by chromosomal translocations of which about 50% are balanced, reciprocal ones. The dominance of chromosomal gains and losses, in particular at early stages during carcinogenesis, suggests that an impairment of chromosome segregation fidelity plays a central role in the genesis of epithelial cancers. Based on this observation we have identified the following problems:* are there abnormalities of cellular structures that regulate chromosome segregation thereby causing the emergence of chromosomal aneuploidy and what role does the centrosome, as the major organizer of the spindle apparatus, have in the proper segregation of chromosomes* is there a karyotypic difference between diploid and aneuploid tumors, and can aberrations in centrosome number and function lead to chromosomal aneuploidy in human and mouse tumors To address these problems we propose to:* develop live cell imaging in combination with the use of green fluorescent protein technology to explore the sequence of chromosomal copy number changes and centrosome aberrations* develop model systems to study the effects of extra copies of specific chromosomes in normal cells - chromosomes, mitosis, centrosomes, - Neither Human Subjects nor Human Tissues

对大量人类和小鼠实体瘤的分析已经确立了基因组不平衡作为上皮起源的癌症中的首要遗传畸变的相关性。所有畸变的95%导致拷贝数变化，反映特定染色体、染色体臂和染色体区域的获得和丢失。因此，实体瘤的细胞遗传学畸变模式不同于血液恶性肿瘤，后者的特征是染色体易位，其中约50%是平衡的、相互的易位。染色体获得和丢失的优势，特别是在癌变的早期阶段，表明染色体分离保真度的损害在上皮癌的发生中起着核心作用。基于这一观察，我们已经确定了以下问题：* 是否存在调节染色体分离的细胞结构异常，从而导致染色体非整倍性的出现，以及作为纺锤体的主要组织者的中心体在染色体的正确分离中具有什么作用 * 二倍体和非整倍体肿瘤之间是否存在核型差异，以及中心体数量和功能的异常是否会导致人类和小鼠肿瘤中的染色体非整倍性。* 开发活细胞成像结合使用绿色荧光蛋白技术，探索染色体拷贝数变化的序列和中心体畸变 * 开发模型系统来研究正常细胞中特定染色体的额外拷贝的影响-染色体，有丝分裂，中心体，