eDyNAmiC - JACKSONLAB

动力 - JACKSONLAB

• 批准号: 10892537
• 负责人: Roel GW Verhaak
• 金额: $ 29.37万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-24 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10892537
• 关键词: Acceleration; Advocate; Affect; Architecture; Blood; Cancer Patient; Cells; Chemicals; Chemistry; Chromosome Pairing; Chromosomes; Collaborations; Communities; Computers; DNA; Data; Diagnostic; Drug Targeting; Drug resistance; Early Diagnosis; Education; Evolution; Family; Fingerprint; Fostering; Funding Mechanisms; Gene Expression Regulation; Gene Order; Generations; Genes; Genetic; Genetic Transcription; Genome; Human; Immune Evasion; Immune system; Immunobiology; Immunologics; Immunology; Immunotherapy; Infrastructure; International; Licensing; Ligands; Maintenance; Malignant Neoplasms; Medicine; Modeling; Monitor; Mutation; Nucleic Acids; Oncogenes; Patients; Pharmaceutical Preparations; Process; Productivity; Research Personnel; Resources; Role; Scientist; Therapeutic; Tissues; Tumor Promotion; Work; Yeast Model System; cancer genomics; cancer heterogeneity; cancer type; combinatorial; epigenomics; experience; extrachromosomal DNA; genome sequencing; innovation; insight; live cell imaging; machine learning algorithm; mathematical model; multiple omics; novel; prevent; programs; time use; tool; tumor; tumor growth; whole genome; yeast genetics

eDyNAmiC (extrachromosomal DNA in Cancer) Human genes are arranged on 23 pairs of chromosomes, but in cancer, tumour-promoting genes can free themselves from chromosomes and relocate to circular, extrachromosomal pieces of DNA (ecDNA). These ecDNA do not follow the normal “rules” of chromosomal inheritance, enabling tumours to achieve far higher levels of cancer-causing oncogenes than would otherwise be possible, and licensing cancers with a way to evolve and change their genomes to evade treatments at rates that would be unthinkable for human cells. The altered circular architecture of ecDNAs also changes the way that the cancer-causing genes are regulated and expressed, further contributing to aggressive tumour growth. These unique features make ecDNA-containing cancers especially aggressive and difficult to treat. Cancer patients whose tumours harbour ecDNA have markedly shorter survival. Despite being first seen over fifty years ago, the critical importance of ecDNA has only recently come to light, and the scale of the problem is substantial. ecDNAs are present in nearly half of all human cancer types and potentially up-to a third of all cancer patients. The collective current understanding of how ecDNA form, how they function, how they move around the cell, how they evolve to resist treatment, how they impact the immune system, and how they can be effectively targeted are lacking. We bring together an internationally recognized, pioneering interdisciplinary team of cancer biologists, geneticists, computer scientists, evolutionary biologists, mathematicians, clinicians, and patient advocates to boldly create novel insights and resources and to provide transformative solutions to one of Cancer’s Grand Challenges. A core team of experienced and productive ecDNA investigators will work with new investigators in the ecDNA and cancer fields to bring completely new perspectives and approaches to this daunting challenge. By bridging cutting-edge and diverse approaches and insights from cancer genomics, yeast genetics, epigenomics, artificial genome synthesis, longitudinal patient tracking, combinatorial and machine learning algorithms, mathematical modelling, immunobiology, and innovative chemistry we will develop a new understanding of the role of ecDNA in cancer, and we will find new ways to drug the undruggable. This bold programme, which consists of 7 work packages and a committed international infrastructure, generates new and unusual collaborations that would simply be impossible under any other type of funding mechanism. Our programme endeavours to foster bold innovative solutions to one of the hardest problems in cancer and to one of the greatest challenges facing cancer patients.

edynanic（癌症外DNA） 人基因被排列在23对染色体上，但是在癌症中，促肿瘤基因可以使自己从染色体中释放，并重新安置为圆形的，外染色体的DNA（ECDNA）。这些ECDNA不遵循染色体遗传的正常“规则”，使肿瘤能够获得比其他可能的更高水平的引起癌症的癌基因，并且以一种将基因组进化和改变其基因组的方式来逃避治疗速率，这对于人类细胞来说是不可思议的。 ECDNA的圆形结构改变也改变了对癌症引起癌症基因的调节和表达的方式，进一步导致了侵袭性肿瘤的生长。这些独特的功能使含ECDNA的癌症特别侵略性且难以治疗。肿瘤携带ecDNA的癌症患者的生存率明显较短。尽管五十年前首次出现，但eCDNA的至关重要性直到最近才亮相，问题的规模很大。 ECDNA几乎存在于所有人类癌症类型中的一半，并且有可能是所有癌症患者的三分之一。集体当前对eCDNA的形成方式，它们的功能，它们如何在细胞周围移动，如何抵抗治疗，如何影响免疫学系统以及如何有效地靶向目标的集体理解。我们将一个国际认可的，开创性的跨学科团队组成的癌症生物学家，遗传学家，计算机科学家，进化生物学家，数学家，临床医生和患者倡导者，以大胆地创建新颖的见解和资源，并为癌症的盛大挑战提供变革性解决方案。由经验丰富且富有成效的ECDNA调查人员组成的核心团队将与ECDNA和癌症领域的新研究人员合作，为这一艰巨的挑战带来全新的观点和方法。通过桥接癌症基因组学，酵母遗传学，表观学，人工基因组合成，纵向患者跟踪，组合和机器学习算法，数学建模，免疫生物学和创新化学的新知识，我们将在癌症中的作用新认识，从而，通过桥接了最先进的方法和农产品方法和分解。这个大胆的计划由7个工作包和一个坚定的国际基础设施组成，产生了新的和不寻常的合作，这些合作在任何其他类型的资金机制下根本不可能。我们的计划努力为癌症中最困难的问题之一和癌症患者面临的最大挑战之一促进大胆的创新解决方案。