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Mechanisms of cell proliferation in whole-genome doubled cells

全基因组加倍细胞的细胞增殖机制

基本信息

批准号：
10467183
负责人：
NEIL J. GANEM
金额：
$ 42.68万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
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/10467183
关键词：
Affect Aging Animal Model Animals Area Biological Biological Models Biology CRISPR-mediated transcriptional activation Cell Line Cell Proliferation Cell Survival Cell model Cells Cellular biology Chromosome abnormality Chromosomes Computer Analysis Computer Models Cues Data Defect Dependence Development Diploid Cells Diploidy Disease Epithelial Cells Event Evolution Frequencies Gene Amplification Gene Deletion Generations Genes Genetic Genomics Goals Growth Hepatocyte Human Image In Vitro Incidence Kinesin Knockout Mice Lethal Genes Maintenance Malignant Neoplasms Methodology Mitotic Mutation Nature Normal Cell Pathologic Pathway interactions Phenotype Physiological Play Ploidies Polyploid Cells Polyploidy Primary Neoplasm Proliferating Research Role Route Solid Neoplasm Testing Therapeutic Tissues Transgenic Mice Tumor Subtype Variant Vertebrates Work base cancer cell design genome analysis human disease human tissue in vivo innovation insight mouse model neoplastic cell new therapeutic target overexpression screening small molecule inhibitor tumor tumorigenesis whole genome

项目摘要

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.

非预定的全基因组加倍事件（WGD）产生与人类相关的多倍体细胞