Mechanisms of cell proliferation in whole-genome doubled cells

全基因组加倍细胞的细胞增殖机制

• 批准号: 10796612
• 负责人: NEIL J. GANEM
• 金额: $ 6.63万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10796612
• 关键词: Affect; Aging; Animal Model; Area; Biological Models; Biology; Cell Proliferation; Cell model; Cells; Cellular biology; Computer Analysis; Computer Models; Defect; Dependence; Development; Diploid Cells; Diploidy; Disease; Event; Evolution; Frequencies; Gene Amplification; Genetic; Goals; Growth; Human; Image; In Vitro; Kinesin; Lethal Genes; Malignant Neoplasms; Methodology; Mitotic; Normal Cell; Pathologic; Phenotype; Play; Ploidies; Polyploid Cells; Proliferating; Role; Solid Neoplasm; Testing; Therapeutic; Tissues; cancer cell; design; human disease; human tissue; in vivo; innovation; insight; small molecule inhibitor; tumor; tumorigenesis; whole genome

Unscheduled whole-genome doubling events (WGD) give rise to polyploid cells that are associated with human disease. Most significantly, WGD generates genetically unstable tetraploid cells that can fuel tumorigenesis. Recent computational analyses have revealed that nearly 40% of all solid tumors have undergone at least one WGD, often early in their development, demonstrating that such events play significant roles in both the initiation and/or progression of human malignancies. Gaining a comprehensive understanding of the mechanisms through which whole-genome doubled cells arise and promote tumorigenesis is therefore a critical, albeit largely unexplored area of cell biology. The goal of this proposal is to combine computational, cell biological, and animal model methodologies to test the overarching hypothesis that whole genome-doubled cells must acquire specific genetic adaptations that enable them to tolerate the numerous defects imparted by doubled DNA content, and that these cells are therefore imparted with specific genetic dependencies that are not present in normal diploid cells (i.e. ploidy-specific lethality). These hypotheses will be tested in three specific aims. Aim 1: Use an innovative approach to rapidly quantitate the frequency and underlying cause of WGD in different tissues in vivo and determine if this frequency is affected by aging. Aim 2: Validate KIF18A, which encodes for a mitotic kinesin, as a ploidy-specific lethal gene in vivo, and use isogenic diploid/tetraploid cell models to perform an imaging- based phenotypic screen to identify small molecule inhibitors of KIF18A. Aim 3: Identify genetic aberrations (e.g. gene amplifications/deletions) that are significantly and specifically enriched in whole genome-doubled tumors, and mechanistically define how such alterations provide ploidy-specific growth advantages in vitro and in vivo. Successful completion of these aims will provide significant insight into the genesis, biology, and evolution of whole-genome doubled cells, as well as potentially reveal new and innovative therapeutic avenues to selectively kill whole-genome doubled cancer cells while sparing the normal healthy diploids from which they arose.

非程序性全基因组加倍事件（WGD）产生与人类染色体畸变相关的多倍体细胞。 疾病最重要的是，WGD产生遗传不稳定的四倍体细胞，可以促进肿瘤发生。 最近的计算分析显示，近40%的实体瘤至少经历了一次 WGD，通常在其发展的早期，表明这些事件在启动和发展过程中起着重要作用。 和/或人类恶性肿瘤的进展。通过以下方式全面了解机制： 因此，全基因组加倍的细胞出现并促进肿瘤发生是一个关键，尽管在很大程度上， 细胞生物学的未知领域。这项提案的目标是将计算、细胞生物学和动物学联合收割机结合起来， 模型方法来测试总体假设，即整个基因组加倍的细胞必须获得特定的 遗传适应，使他们能够容忍DNA含量加倍所带来的许多缺陷， 这些细胞因此被赋予了在正常二倍体中不存在的特定遗传依赖性， 细胞（即倍性特异性致死率）。这些假设将在三个具体目标中得到检验。目标1：使用 快速定量体内不同组织中WGD频率和根本原因的创新方法 并确定该频率是否受到老化的影响。目的2：KIF 18 A，编码有丝分裂驱动蛋白， 作为体内倍性特异性致死基因，并使用等基因二倍体/四倍体细胞模型进行成像- 基于表型筛选以鉴定KIF 18 A的小分子抑制剂。目标3：识别遗传畸变（例如， 基因扩增/缺失）在全基因组加倍肿瘤中显著且特异性富集， 并机械地定义了这种改变如何在体外和体内提供倍性特异性生长优势。 这些目标的成功完成将提供重要的洞察力的起源，生物学，和进化的 全基因组加倍细胞，以及潜在地揭示新的和创新的治疗途径，以选择性地 杀死全基因组加倍的癌细胞，同时保留产生它们的正常健康二倍体。