Understanding proteome remodeling in aneuploidy

了解非整倍体中的蛋白质组重塑

• 批准号: 10407511
• 负责人: Yansheng Liu
• 金额: $ 37.69万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10407511
• 关键词: Affect; Aneuploid Cells; Aneuploidy; Benchmarking; Biochemical; Biological; Biological Markers; CISH gene; CRISPR/Cas technology; Cell Lineage; Cell model; Cells; Characteristics; Chromosomes; Collaborations; Complex; Data; Data Set; Development; Disease; Disease Management; Dosage Compensation (Genetics); Down Syndrome; Embryo; Epithelial Cells; Excision; Fibroblasts; Foundations; Gene Dosage; Gene Expression; Gene Expression Profiling; Genes; Genetic Diseases; Genome; Genomics; Genotype; Goals; Hela Cells; Homeostasis; Human; Human Genetics; Individual; Interferons; Lead; Light; Literature; Location; Lung; Malignant Neoplasms; Malignant neoplasm of lung; Mass Spectrum Analysis; Measurement; Messenger RNA; Modeling; Molecular; Molecular Conformation; Molecular Sieve Chromatography; Monozygotic twins; Mus; Pathology; Pathway interactions; Patients; Phenotype; Play; Post-Transcriptional Regulation; Process; Proteins; Proteome; Proteomics; Reproducibility; Research; Role; Signal Pathway; Signal Transduction; Squamous Cell Lung Carcinoma; Stress; Structure; System; Techniques; Therapeutic; Transcription Process; Trisomy; Work; base; cellular targeting; clinical phenotype; data acquisition; density; disease phenotype; dosage; experience; fitness; genome-wide; improved; individual variation; novel; protein expression; protein function; protein protein interaction; proteostasis; response; tool

ABSTRACT Unbalanced chromosome content, so-called aneuploidy, is a hallmark of many human genetic diseases and cancers. Aneuploidy not only results in the altered expression of the genes encoded on the aneuploid chromosome, but also affects gene expression genome-wide. For many aneuploidy related diseases, it is still not clear which gene or gene sets are the key drivers of disease pathology. Research on molecular consequences of aneuploidy could shed invaluable light on “genotype-phenotype” association, thus leading to a better understanding of disease development mechanisms. Due to the known substantial post-transcriptional processes in aneuploidy condition and the functional importance of proteins, proteomic measurement is indispensable to identify genes that are dosage-imbalanced at the protein level. However, biological and technical challenges such as the variability of the individual genome, the limited quantitative reproducibility and accuracy of the measurement, and the lack of strategies for identifying indirect mechanisms have hindered efficient proteomic scrutiny on aneuploidy. We hypothesize that the aneuploid cells would employ characteristic proteostasis and cell signaling pathways to deal with the large-scale protein dosage imbalance, and that the newly acquired or altered protein-protein interactions under aneuploidy stress play an important role in regulating molecular network and cellular fitness. In this proposal, we will use isogenic cell models from human and mouse aneuploidy cases. We will further develop and apply the techniques based on quantitative mass spectrometry and new analytical strategies based on protein- context profiling to discover the direct and indirect proteomic effects in the aneuploidy models. Results from this proposal are extremely important. First, the proteomic- centric, multilayered dataset will describe how protein homeostasis is maintained when several hundreds of genes that are gained or lost, decipher commonly activated signaling processes across aneuploidy models, and provide opportunities to predict the cellular impact of specific gene copy number alteration (CNA). Second, the protein-context profiling technique will be an invaluable tool for identifying de novo protein functions and associations in aneuploidy and other disease conditions. Third, those significant proteins escaping the homeostasis control or tightly interacting to signaling hubs will provide a list of important protein targets for further functional studies in aneuploidy cases, such as lung squamous cell carcinomas and trisomy disorders that are relevant to the studied cell models.

摘要 染色体含量不平衡，即所谓的非整倍体，是许多人类遗传病和 癌症。非整倍体不仅会导致非整倍体上编码的基因表达发生变化 染色体，但也影响全基因组的基因表达。对于许多非整倍体相关疾病来说，它仍然是 不清楚哪些基因或基因组是疾病病理的关键驱动因素。分子生物学的研究进展 非整倍体的后果可以为“基因-表型”关联提供宝贵的信息，从而导致 更好地了解疾病的发展机制。由于已知的大量转录后转录 在非整倍体条件下的过程和蛋白质的功能重要性，蛋白质组学测量是 对于识别在蛋白质水平上剂量不平衡的基因来说是必不可少的。然而，生物和 技术挑战，如个体基因组的变异性，有限的定量重复性和 衡量的准确性，以及缺乏确定间接机制的战略，都阻碍了 对非整倍体的有效蛋白质组学研究。我们假设非整倍体细胞将利用 蛋白质平衡和细胞信号通路来处理大规模的蛋白质剂量失衡，并认为 在非整倍体胁迫下新获得或改变的蛋白质-蛋白质相互作用在 调节分子网络和细胞适合性。在这项提案中，我们将使用人类的等基因细胞模型 和小鼠非整倍体病例。我们将进一步开发和应用基于定量质量的技术 光谱和基于蛋白质上下文简档的新分析策略，以发现直接和 非整倍体模型中的间接蛋白质组学效应。这项提案的结果极其重要。第一, 以蛋白质组为中心的多层数据集将描述当几个 数百个基因的获得或丢失，破译了共同激活的信号过程 非整倍体模型，并提供了预测特定基因拷贝数对细胞影响的机会 变更(CNA)。其次，蛋白质上下文描述技术将是识别De的无价工具。 Novo蛋白在非整倍体和其他疾病条件下的功能和联系。第三，那些有意义的 逃离动态平衡控制或与信号中枢紧密相互作用的蛋白质将提供一系列重要的 在非整倍体病例中进一步功能研究的蛋白质靶点，如肺鳞状细胞癌和 与所研究的细胞模型相关的三体障碍。