Identification of genetic collaborators in cancer with a brca2-mutant zebrafish model

利用 brca2 突变斑马鱼模型鉴定癌症的遗传合作者

基本信息

批准号：
9920485
负责人：
Heather R. Shive
金额：
$ 12.69万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9920485
关键词：
Address Affect Alleles Anatomy Aneuploidy Animal Cancer Model Animal Model Apoptosis Applications Grants Architecture Automobile Driving Award BRCA2 Mutation BRCA2 gene Biological Assay Biomedical Research Board Certification Candidate Disease Gene Comparative Genomic Analysis Complex DNA Damage DNA Sequence Alteration Data Development Development Plans Diagnosis Doctor of Philosophy Doctor of Veterinary Medicine Event Exhibits Funding Future Genes Genetic Genome engineering Genomic Instability Genomic Segment Genomics Goals Heritability Human Link Malignant Neoplasms Mediating Mentored Research Scientist Development Award Mentorship Modeling Molecular Mutation North Carolina Oncogenes Outcome Pathology Pathway interactions Phenotype Ploidies Positioning Attribute Recurrence Recurrent Malignant Neoplasm Research Role Scientist Somatic Mutation TP53 gene Testing Therapeutic Intervention Time Training Transgenic Organisms Universities Veterinary Medicine Zebrafish actionable mutation cancer diagnosis cancer risk cancer therapy carcinogenesis career career development college combinatorial comparative genomic hybridization design human data in vivo insight mutant mutational status new therapeutic target novel novel diagnostics public health relevance research and development tool tumor progression

项目摘要

DESCRIPTION (provided by applicant): The genetic complexity of cancers impedes identification of key genetic collaborators in carcinogenesis, presenting a critical barrier to the discovery of new diagnostic or therapeutic targets. Heritable mutations in known cancer-associated genes, such as BRCA2, are strongly linked to cancer risk. However, numerous additional collaborating mutations that are somatically acquired contribute significantly to cancer development. Additional mutations in cancers are often generated through amplification and deletion events (copy number alterations; CNA). CNA can span large genomic regions and impact multiple genes, which obscures the identity of driver mutations in carcinogenesis. By defining recurrent cancer-associated CNA in an animal model such as the zebrafish, and comparing these data to known CNA in human cancers, we can use differences in genomic architecture between species to identify genes that are frequently disrupted in cancers from both species. This approach thus identifies novel, conserved, candidate driver genes that can be easily assessed in the zebrafish model for their potential to impact carcinogenesis. The goal for this proposal is to identify and functionally characterize conserved genes that are recurrently disrupted by CNA in BRCA2-associated human and zebrafish cancers. We have previously shown genetic similarities between human and zebrafish BRCA2-associated cancers, which include the collaborative role for tp53 in brca2-associated carcinogenesis and the loss of the wildtype alleles for brca2 and/or tp53 in cancers. Our central hypothesis is that novel, conserved, candidate driver genes that collaborate in BRCA2-associated carcinogenesis will be revealed through comparative genomics analyses of human and zebrafish BRCA2-associated cancers. In vivo characterization of these candidate genes in zebrafish will provide insight into how they modulate cellular events of direct relevance to cancer development, and will guide initiation of stable transgenic and mutant zebrafish lines for use in future carcinogenesis studies Our long-term goal is to define key conserved combinatorial gene disruptions and novel molecular pathways that drive cancer progression. The candidate for this K01 Research Career Award is a D.V.M./Ph.D. scientist with board certification in Veterinary Anatomic Pathology. The research proposed in this grant application will be performed at North Carolina State University, College of Veterinary Medicine, under the mentorship of Dr. Robert Smart, Dr. Matthew Breen, and Dr. Jeffrey Yoder. The candidate is committed to a career in biomedical research, and seeks the additional training, mentorship, and protected research time provided by the proposed research and career development plan to facilitate her transition to an independent academic career.

描述（应用程序提供）：癌症的遗传复杂性阻碍了致癌作用中关键遗传合作者的识别，这给了癌症发现新的诊断或治疗靶标。已知的癌症相关基因（例如BRCA2）中可遗传的突变与癌症风险密切相关。但是，在体外获得的许多其他协作突变为癌症做出了重大贡献发展。癌症中的其他突变通常是通过扩增和缺失事件（拷贝数变化； CNA）产生的。 CNA可以跨越大的基因组区域并影响多个基因，这掩盖了癌变中驱动突变的身份。通过在诸如斑马鱼等动物模型中定义复发性癌症相关的CNA，并将这些数据与人类癌中的已知CNA进行比较，我们可以在物种之间使用基因组结构的差异来识别这两种癌症中经常破坏的基因。因此，这种方法确定了可以在斑马鱼模型中轻松评估的新颖，配置的候选驱动基因，以影响癌变。该提案的目标是识别并在功能上表征已反复的配置基因在BRCA2相关的人类和斑马鱼癌中被CNA破坏。我们先前已经显示了人类和斑马鱼BRCA2相关的癌症之间的遗传相似性，其中包括TP53在BRCA2相关的致癌作用中的协作作用以及癌症中BRCA2和/或TP53的Wildtype等位基因的丧失。我们的中心假设是，将通过对人类和斑马鱼BRCA2相关癌症的比较基因组学分析来揭示新颖的，配置的，候选的驱动基因，这些基因在BRCA2相关的癌变中进行了合作。斑马鱼中这些候选基因的体内表征将提供有关它们如何调节与癌症发育直接相关的细胞事件的洞察力，并将指导稳定的转基因和突变斑马鱼线的启动，用于未来的致癌研究，我们的长期目标是定义关键的组合基因组合基因和新颖的形成形成的形成癌症。该K01研究职业奖的候选人是D.V.M./PH.D。兽医解剖病理学董事会认证的科学家。本赠款申请中提出的研究将在北卡罗来纳州立大学，兽医学院，在罗伯特·斯玛特博士，马修·布雷恩博士和杰弗里·约德博士的心态下进行。候选人致力于生物医学研究的职业，并寻求拟议的研究和职业发展计划提供的额外的培训，指导和受保护的研究时间，以促进她过渡到独立的学术生涯。