Exploring the mechanism and function of somatic homolog pairing

探索体细胞同源配对的机制和功能

• 批准号: 8548919
• 负责人: Eric F. Joyce
• 金额: $ 5.39万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-10-01 至 2014-09-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8548919
• 关键词: 19q; Address; Biological Assay; Cell Culture System; Cell Culture Techniques; Cell Nucleus; Cell division; Cell physiology; Cells; Cessation of life; Chromatin Structure; Chromosome 19; Chromosome Positioning; Chromosome Structures; Chromosome abnormality; Chromosomes; Deformity; Development; Disease; Drosophila genome; Drosophila genus; Employee Strikes; Event; Fluorescent in Situ Hybridization; Gene Activation; Gene Expression; Gene Expression Regulation; Gene Silencing; Genes; Genetic; Genetic Crossing Over; Genetic Transcription; Genome; Genomics; Goals; Homologous Gene; Human; Human Characteristics; Human Chromosomes; Human Development; Human Genome; Immune system; Institutional Review Boards; Laboratories; Lead; Learning; Length; Light; Loss of Heterozygosity; Malignant Neoplasms; Mediating; Mitotic; Mutation; Neoplasm Metastasis; Open Reading Frames; Outcome; Pathway interactions; Play; Positioning Attribute; Process; Public Health; RNA Interference; Renal Oncocytoma; Repression; Signal Transduction; Sister Chromatid; Somatic Cell; Specificity; Structure; Surveys; T-Cell Development; Testing; Tumor Cell Line; X Chromosome; X Inactivation; Y Chromosome; anticancer research; arm; base; cancer prevention; cell transformation; cohesion; gene function; genome-wide; human disease; medical schools; mutant; neoplastic cell; screening; sperm cell; tumor; tumorigenesis

DESCRIPTION (provided by applicant): The human genome is made up of two copies of each chromosome that are stored within the nucleus of cells. In addition to their number and structure, the position and spatial dynamics of chromosomes are under tight control. There is abundant evidence that direct interactions between chromosomes can be supported and even contribute to the activation or repression of several genes. My studies will focus on a particular type of interaction, that which occurs between maternal and paternal copies of chromosomes, known as homolog pairing. Many pairing-driven processes are essential for human development and can cause disease when gone awry, with outcomes ranging from cancers to compromised immune systems, physical deformities, and death. While a tremendous amount has been learned about the need of pairing on downstream homology- driven processes, almost nothing is known about how homologous chromosome segments find each other, physically align and then form stable pairing interactions within cells. The primary goal of this proposal is to identify and characterize the factors and mechanisms that mediate homolog pairing (Aims 1 and 2). Taking advantage of the fact that homologous chromosomes are intimately paired along their entire length in Drosophila cells, I will screen for mutations that decrease the fidelity of homolog pairing and then characterize the genetic pathways that are identified. Ultimately, the characterization of the genes underlying homolog pairing will not only shed light on the mechanism of pairing itself, but also the mechanisms of pairing-mediated processes that have implications for human development and disease. The process of homolog pairing is particularly relevant to cancer research, as these interactions can lead to dramatic changes in gene expression and may, therefore, contribute to the formation of some tumors. Striking evidence for this has recently been observed in human cells, wherein the maternal and paternal copies of the q arm of human Chromosome 19 inappropriately pair along its entire length in renal oncocytomas. This study raises the very new and exciting possibility that the state of homolog pairing is directly related to cancer. To better understand the impact of chromosomal interactions in the context of cancer, I will therefore also survey a wide variety of tumor cells for their ability to support homolog pairing (Aim 3). If pairing is observed outside of renal oncocytomas, it will indicate that changes in chromosome positioning, in addition to numerical and structural abnormalities, should be considered as an event associated with tumor formation and a new target for the treatment and prevention of cancer.

描述（由申请人提供）：人类基因组由储存在细胞核内的每条染色体的两个拷贝组成。除了它们的数量和结构，染色体的位置和空间动态也受到严格控制。有大量的证据表明，染色体之间的直接相互作用可以支持，甚至有助于激活或抑制几个基因。我的研究将集中在一种特殊类型的相互作用上，这种相互作用发生在染色体的母系和父系副本之间，称为同源配对。许多配对驱动的过程对人类发展至关重要，如果出错，可能会导致疾病，结果从癌症到免疫系统受损，身体畸形和死亡。 虽然已经了解了大量关于下游同源性驱动过程中配对的需要，但几乎不知道同源染色体片段如何找到彼此，物理对齐，然后在细胞内形成稳定的配对相互作用。该提案的主要目标是确定和表征介导同源配对的因素和机制（目标1和2）。利用果蝇细胞中同源染色体沿其全长沿着紧密配对的事实，我将筛选降低同源配对保真度的突变，然后表征所鉴定的遗传途径。最终，同源配对基因的表征不仅将揭示配对本身的机制，而且还将揭示对人类发育和疾病有影响的配对介导过程的机制。 同源配对的过程与癌症研究特别相关，因为这些相互作用可能导致基因表达的巨大变化，因此可能有助于某些肿瘤的形成。最近在人细胞中观察到了这方面的显著证据，其中在肾嗜酸细胞瘤中，人染色体19的q臂的母本和父本拷贝沿其全长不适当地沿着配对。这项研究提出了一个非常新的和令人兴奋的可能性，即同源配对的状态与癌症直接相关。为了更好地理解染色体相互作用在癌症背景下的影响，我还将调查各种肿瘤细胞支持同源配对的能力（目的3）。如果在肾嗜酸细胞瘤之外观察到配对，则表明除了数量和结构异常之外，染色体定位的变化应被视为与肿瘤形成相关的事件以及治疗和预防癌症的新靶点。