Core 2: Mammalian Artificial Chromosome (MAC)

核心 2：哺乳动物人工染色体 (MAC)

• 批准号: 10626286
• 负责人: Ben E. Black
• 金额: $ 36.48万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-08 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10626286
• 关键词: Address; Animals; Artificial Human Chromosomes; Artificial Mammalian Chromosomes; Award; Biology; Cancer Biology; Categories; Cell Cycle; Cell division; Cells; Centromere; Chemicals; Chromatin; Chromatin Modeling; Chromosome Segregation; Chromosomes; Cloning; Cytoplasm; DNA; DNA Damage; DNA Sequence; DNA cassette; DNA sequencing; Engineered Gene; Engineering; Epigenetic Process; Essential Genes; Event; Gene Dosage; Generations; Genes; Genetic; Genetic Recombination; Genome; Genomic Instability; Genomics; Housing; Human Genome; Individual; Inherited; Lead; Mitosis; Mitotic; Mitotic Chromosome; Molecular; Molecular Biology; Monitor; Mus; Nature; Organoids; Outcome; Process; Proteins; Regulatory Element; Reporter; Reporting; Saccharomycetales; Sister Chromatid; Site; System; Technology; Work; anti-tumor immune response; cell type; chemical genetics; chromosome missegregation; design; design and construction; embryonic stem cell; epigenomics; experimental study; falls; flexibility; genetic information; genetic payload; genomic locus; immunoregulation; improved; innovation; member; micronucleus; next generation; patient response; predictive marker; programs; response; segregation; synthetic biology; therapy resistant; tool; tumor

The mammalian artificial chromosome (MAC) Core will support the overall Project, which seeks to address the downstream consequences in cells and animals of DNA damage, the causes and consequences of chromosome missegregation at cell division, and the mechanisms that drive these processes in tumors. It will serve as a foundry for MACs that will support each of the individual projects that require chromosome manipulations and engineering: from site-directed and inducible DNA damage, to reporters for chromosome segregation errors, to housing the genetically encoded components of a chemical genetics toolbox. MACs can carry large (i.e. 100-2000 kb) genetic payloads, and exist in cells as molecules that are propagated and inherited alongside the natural chromosomes. Their autonomous nature is a key advantage, since they deliver their genetic payloads without insertion or other disruption of the host genome. The Core will employ our recent innovations in MAC technology that gave rise to a new generation of MAC templates in which we direct the seeding of centromeric chromatin. This approach permits efficient MAC formation on diverse DNA templates. The Core will undertake MAC approaches from their design, creation, delivery into cells, characterization, through to their implementation for experiments proposed in the individual Projects of the program. Specifically, the Core will develop and use MACs that fall into the following categories: ones that serve as targets for DNA damage, ones that harbor elaborate genetic payloads that will modulate chromosome segregation with a high degree of sophistication, and ones that carry fluorescent reporters of chromosome missegregation. The MAC Core is designed to be flexible to help Project members develop new lines of experimentation that arise from the findings achieved during the initial steps in the overall program.

哺乳动物人工染色体（MAC）核心将支持整个项目，该项目旨在解决 DNA损伤的细胞和动物的下游后果， 细胞分裂时的染色体错误分离，以及在肿瘤中驱动这些过程的机制。它将 作为MAC的铸造厂，将支持每个需要染色体的单独项目 操作和工程：从定点和诱导型DNA损伤，到染色体报告基因 分离错误，以容纳化学遗传学工具箱的遗传编码组件。MAC可以 携带大的（即100-2000 kb）遗传有效载荷，并作为增殖和 与自然染色体一起遗传。他们的自主性是一个关键的优势，因为他们提供 它们的遗传有效载荷而不插入或破坏宿主基因组。核心会雇佣我们最近的 MAC技术的创新，产生了新一代MAC模板，我们在其中指导 着丝粒染色质的接种。这种方法允许在不同的DNA模板上有效地形成MAC。 核心将承担MAC方法，从他们的设计，创造，交付到细胞，表征， 通过他们的实施，在该计划的个别项目提出的实验。具体地说， “核心”将开发和使用可分为以下几类的MAC：作为DNA靶点的MAC 损害，那些窝藏精心设计的遗传有效载荷，将调节染色体分离与高 复杂程度，和那些携带染色体错误分离的荧光报告。的MAC 核心是设计灵活，以帮助项目成员开发新的实验线，产生于 在整个方案的最初阶段取得的成果。