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：
10409852
负责人：
Heather R. Shive
金额：
$ 9.68万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10409852
关键词：
Address Affect Alleles Anatomy Aneuploidy Animal Cancer Model Animal Model Apoptosis Architecture Automobile Driving Award BRCA2 Mutation BRCA2 gene Biological Assay Biomedical Research Board Certification Candidate Disease Gene Comparative Genomic Analysis Complex Comprehensive Cancer Center DNA Damage DNA Sequence Alteration Data Development Development Plans Diagnosis Doctor of Philosophy 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 Ohio Oncogenes Outcome Pathology Pathway interactions Phenotype Ploidies Positioning Attribute Recurrence Recurrent Malignant Neoplasm Research Research Project Grants Role Scientist Somatic Mutation TP53 gene Testing Therapeutic Intervention Time Training Transgenic Organisms Universities Veterinary Medicine Zebrafish cancer diagnosis cancer risk cancer therapy carcinogenesis career career development college combinatorial comparative genomic hybridization design human data in vivo insight mutant mutational status novel research and development tool tumor progression

Address Affect Alleles Anatomy Aneuploidy Animal Cancer Model Animal Model Apoptosis Architecture Automobile Driving Award BRCA2 Mutation BRCA2 gene Biological Assay Biomedical Research Board Certification Candidate Disease Gene Comparative Genomic Analysis Complex Comprehensive Cancer Center DNA Damage DNA Sequence Alteration Data Development Development Plans Diagnosis Doctor of Philosophy 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 Ohio Oncogenes Outcome Pathology Pathway interactions Phenotype Ploidies Positioning Attribute Recurrence Recurrent Malignant Neoplasm Research Research Project Grants Role Scientist Somatic Mutation TP53 gene Testing Therapeutic Intervention Time Training Transgenic Organisms Universities Veterinary Medicine Zebrafish cancer diagnosis cancer risk cancer therapy carcinogenesis career career development college combinatorial comparative genomic hybridization design human data in vivo insight mutant mutational status novel research and development tool tumor progression

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项目摘要

Project Summary/Abstract The genetic complexity of cancers impedes identification of key genetic collaborators in carcinogenesis. Heritable mutations in known cancer-associated genes, such as BRCA2, are strongly linked to cancer risk. However, somatically acquired mutations contribute significantly to cancer progression. These additional mutations are often generated through amplification and deletion events (copy number alterations; CNA). CNA can span large genomic regions and disrupt numerous genes, which impedes identification of cancer drivers. 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 recurrently disrupted genes 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 wild type 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. This K01 Research Career Award recipient is a DVM/PhD. scientist with board certification in Veterinary Anatomic Pathology. The K01 research project was performed at North Carolina State University, College of Veterinary Medicine (years 1-3), under the mentorship of Dr. Robert Smart, Dr. Matthew Breen, and Dr. Jeffrey Yoder, and is currently being performed at the Ohio State University, College of Veterinary Medicine under the mentorship of Dr. Ramesh Ganju (OSU Comprehensive Cancer Center) and continued mentorship of Drs. Smart, Breen, and Yoder. The candidate is committed to a career in biomedical research, and seeks the additional training, mentorship, and protected research time provided by this research and career development plan to facilitate her transition to an independent academic career.

项目摘要/摘要癌症的遗传复杂性阻碍了致癌作用中关键遗传合作者的鉴定。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，体外获得的突变对癌症的进展产生了重大贡献。这些额外突变通常是通过扩增和缺失事件（拷贝数变化； CNA）产生的。 CNA 可能跨越大型基因组区域并破坏许多基因，这阻碍了对癌症驱动因素的识别。经过在斑马鱼等动物模型中定义复发性癌症相关的CNA，并比较这些数据对于人类癌症中已知的CNA，我们可以使用物种之间基因组结构的差异来识别两种物种的癌症中反复破坏了基因。因此，这种方法确定了新颖，保守的，可以在斑马鱼模型中轻松评估其影响的候选驱动器基因致癌作用。该建议的目标是识别并在功能上表征保守基因在BRCA2相关的人和斑马鱼癌中，CNA反复破坏。我们以前显示了人与斑马鱼BRCA2相关癌症之间的遗传相似性，其中包括协作 TP53在BRCA2相关的致癌作用中的作用以及BRCA2和/或TP53中野生型等位基因的损失癌症。我们的中心假设是在BRCA2-合作的新颖，保守的候选驱动器基因相关的癌变将通过人类和斑马鱼的比较基因组学分析来揭示 BRCA2相关的癌症。这些候选基因在斑马鱼中的体内表征将提供洞察力它们如何调节与癌症发展直接相关的细胞事件，并将指导开始稳定的转基因和突变斑马鱼线用于未来的致癌研究。我们的长期目标是定义关键保守的组合基因破坏和驱动癌症的新型分子途径进展。这个K01研究职业奖获得者是DVM/博士学位。具有董事会认证的科学家兽医解剖病理学。 K01研究项目是在北卡罗来纳州立大学进行的兽医学院（1 - 3年），在罗伯特·斯玛特（Robert Smart），马修·布雷恩（Matthew Breen）博士的指导下杰弗里·约德（Jeffrey Yoder）博士，目前正在俄亥俄州立大学兽医学院进行在Ramesh Ganju博士（OSU综合癌症中心）的指导下，并继续指导博士。聪明，布雷恩和Yoder。候选人致力于生物医学研究的职业，并寻求这项研究和职业发展提供的其他培训，指导和受保护的研究时间计划促进她过渡到独立的学术生涯。