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

• 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
• 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

 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（由申请人提供）：癌症的遗传复杂性阻碍了对致癌作用中关键遗传合作者的识别，对癌症的治疗构成了关键障碍。 发现新的诊断或治疗靶点。已知癌症相关基因（如BRCA 2）中的遗传突变与癌症风险密切相关。然而，体细胞获得的许多其他协作突变对癌症有显著贡献。 发展癌症中的其他突变通常通过扩增和缺失事件（拷贝数改变; CNA）产生。CNA可以跨越大的基因组区域并影响多个基因，这掩盖了致癌过程中驱动突变的身份。通过在动物模型（如斑马鱼）中定义复发性癌症相关的CNA，并将这些数据与人类癌症中已知的CNA进行比较，我们可以利用物种之间基因组结构的差异来识别两个物种癌症中经常被破坏的基因。因此，这种方法确定了新的，保守的，候选的驱动基因，可以很容易地在斑马鱼模型中评估其影响致癌作用的潜力。该提案的目标是鉴定和功能性地表征重复表达的保守基因。 在BRCA 2相关的人类和斑马鱼癌症中被CNA破坏。我们先前已经显示了人类和斑马鱼BRCA 2相关癌症之间的遗传相似性，其中包括tp 53在brca 2相关致癌作用中的协同作用以及brca 2和/或tp 53在癌症中野生型等位基因的丢失。我们的中心假设是，新的，保守的，候选的驱动基因在BRCA 2相关的致癌作用合作将通过人类和斑马鱼BRCA 2相关癌症的比较基因组学分析揭示。这些候选基因在斑马鱼体内的特性将提供洞察他们如何调节细胞事件的直接相关的癌症发展，并将指导启动稳定的转基因和突变斑马鱼线用于未来的致癌研究我们的长期目标是确定关键的保守组合基因破坏和新的分子途径，推动癌症的进展。K 01研究职业奖的候选人是D.V.M./博士兽医解剖病理学委员会认证的科学家。本资助申请中提出的研究将在北卡罗来纳州州立大学兽医学院进行，由Robert Smart博士、Matthew Breen博士和Jeffrey Yoder博士指导。候选人致力于生物医学研究的职业生涯，并寻求拟议的研究和职业发展计划提供的额外培训，指导和受保护的研究时间，以促进她向独立学术生涯的过渡。