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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

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.

项目总结/摘要癌症的遗传复杂性阻碍了对致癌过程中关键遗传合作者的识别。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，体细胞获得性突变显著促进癌症进展。这些额外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破坏许多基因，这阻碍了癌症驱动因素的识别。通过在动物模型如斑马鱼中定义复发性癌症相关的CNA，并比较这些数据对于已知的人类癌症中的CNA，我们可以利用物种之间基因组结构的差异来识别在这两个物种的癌症中反复破坏的基因。因此，这种方法鉴定了新的，保守的，候选驱动基因，可以很容易地在斑马鱼模型中评估其影响的潜力致癌作用该建议的目标是鉴定和功能表征保守基因，在BRCA 2相关的人类和斑马鱼癌症中被CNA反复破坏。我们先前已经表明人类和斑马鱼BRCA 2相关癌症之间的遗传相似性，其中包括协作 tp 53在brca 2相关的致癌作用中的作用以及brca 2和/或tp 53在癌的我们的中心假设是，在BRCA 2 - 3中协作的新的、保守的候选驱动基因，相关的致癌作用将通过人类和斑马鱼的比较基因组学分析揭示 BRCA 2相关癌症这些候选基因在斑马鱼体内的特性将提供洞察研究它们如何调节与癌症发展直接相关的细胞事件，并将指导稳定的转基因和突变的斑马鱼品系，用于未来的致癌研究。我们的长期目标是定义关键的保守组合基因破坏和驱动癌症的新分子途径进展这个K 01研究职业奖获得者是一个DVM/博士。科学家与董事会认证，兽医解剖病理学K 01研究项目在北卡罗来纳州州立大学进行，兽医学院（1-3年），在罗伯特·斯马特博士，马修·布林博士的指导下，博士杰弗里约德，目前正在执行在俄亥俄州州立大学，兽医学院在Ramesh Ganju博士（OSU综合癌症中心）的指导下， Drs.斯马特布林和约德候选人致力于生物医学研究的职业生涯，并寻求本研究和职业发展提供的额外培训、指导和受保护的研究时间计划帮助她过渡到一个独立的学术生涯。