"Comparative gene resequencing in mouse cancer models"

“小鼠癌症模型中的比较基因重测序”

基本信息

批准号：
8706084
负责人：
David Glenn McFadden
金额：
$ 3.71万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8706084
关键词：
Adenocarcinoma Cell Affect Bioinformatics Cancer Biology Cancer Model Cancer Patient Candidate Disease Gene Caring Cell Culture Techniques Cell Line Cell Transplantation Cell physiology Cessation of life Code Comparative Study Critiques Cultured Cells DNA Resequencing DNA Sequence DNA copy number Data Data Set Development Disseminated Malignant Neoplasm Endocrinology Environment Evolution Exhibits Gene Expression Profile Genes Genetic Genetic Engineering Genetically Engineered Mouse Genome Genomics Human Human Cell Line Hyperplasia In Vitro Individual Internal Medicine International Large-Scale Sequencing Lentivirus Vector Lung Adenocarcinoma Malignant Neoplasms Malignant neoplasm of thyroid Massive Parallel Sequencing Mediating Mediator of activation protein Mentors Mentorship Methodology Modeling Mus Mutation Mutation Spectra Neoplasm Metastasis Neoplasms Oncogenes Pathway interactions Phenotype Play Point Mutation Role Somatic Mutation Staging Therapeutic Intervention Tissue Banking Tissue Banks Training Training Support Tumor Cell Line Work Writing anticancer research base cDNA Expression cancer cell cancer genome cancer genomics career development clinical practice comparative comparative genomics exome genetic technology human cancer mouse model improved in vivo interest meetings mouse model mutant new technology novel pressure research study small hairpin RNA tumor tumor initiation tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): This Career Development proposal will support the training of Dr. David McFadden in mouse cancer models and genomics under the mentorship of Dr. Tyler Jacks with support from collaborators Drs. Meyerson, Hannon, Lander, and Getz. The candidate, Dr. McFadden, is trained in mouse genetics, internal medicine and endocrinology with a clinical practice devoted to the care of thyroid cancer patients. The mentor, Dr. Jacks, is an international leader in cancer research with a focus on the development and use of sophisticated mouse cancer models. Drs. Meyerson, Hannon, Lander, and Getz bring a wealth of expertise in human lung adenocarcinoma genetics, genomics, and bioinformatics. In this unique scientific environment, Dr. McFadden will have the opportunity to train in cancer biology and genomics in order to blend mouse cancer models with cutting edge genetic technology in order to identify novel targets for treatment in human cancer. The development of massively parallel DNA sequencing methodologies has fueled the detailed description of human cancer genomes. However, the functional relevance of specific mutations to the cancer phenotype has been more challenging to define. Carefully constructed mouse models of human cancer have been developed and utilized to carefully characterize all stages of tumorigenesis, including tumor initiation, progression, and metastasis. Although the genetically engineered mutations responsible for tumor induction in these models are known ab initio, the spectrum of mutations acquired during progression from hyperplasia to invasive neoplasm remains largely unknown. Studies have demonstrated that carefully constructed mouse models exhibit gene expression signatures and DNA copy number profiles that overlap with those detected in human cancers, suggesting that the selective pressures exerted on cancer cells are shared between mice and humans. These studies demonstrate the value of cross-species comparisons to identify functionally important driver genes that direct the diverse cellular processes that compose human cancer progression. Over this 5-year proposal, we will generate large-scale sequencing datasets from a mouse model of lung adenocarcinoma to identify the point mutations acquired during tumor evolution. We will perform cross- species comparative studies and pathway analyses to rank candidate genes and pathways of most interest, and precisely characterize the functional role of these alterations using genetically engineered mouse models and human cancer cells. Our preliminary data demonstrate that this approach is feasible. We have generated a murine lung adenocarcinoma tissue bank consisting of advanced, high-grade murine tumors, cell lines, and metastases and developed a hybridization-based enrichment platform for the capture and sequencing of cancer-relevant genes. Using this novel technology, we have sequenced murine lung adenocarcinoma cell lines and identified somatic mutations acquired during tumor progression.

描述（由申请人提供）：该职业发展建议将在泰勒·杰克斯（Tyler Jacks）博士的指导下支持戴维·麦克法登（David McFadden）博士在小鼠癌症模型和基因组学中的培训，并在合作者DRS的支持下。 Meyerson，Hannon，Lander和Getz。候选人McFadden博士接受了小鼠遗传学，内科和内分泌学的培训，其临床实践致力于护理甲状腺癌患者。这位导师杰克（Jacks）博士是癌症研究的国际领导者，着重于复杂的小鼠癌症模型的开发和使用。博士。 Meyerson，Hannon，Lander和Getz在人类肺腺癌，基因组学和生物信息学方面带来了丰富的专业知识。在这个独特的科学环境中，麦克法登博士将有机会培训癌症生物学和基因组学，以便将小鼠癌模型与尖端遗传技术融合在一起，以确定人类癌症治疗的新颖目标。大规模平行的DNA测序方法的发展促进了人类癌症基因组的详细描述。但是，特定突变与癌症表型的功能相关性更为具有挑战性。精心构造的人类癌症的小鼠模型已被开发和利用，以仔细表征肿瘤发生的所有阶段，包括肿瘤的启动，进展和转移。尽管在这些模型中造成肿瘤诱导的基因工程突变是已知的，但在从增生到侵入性肿瘤的过程中获得的突变谱仍然很大程度上是未知的。研究表明，经过精心构造的小鼠模型表现出基因表达特征和DNA拷贝数曲线，与人类癌症中发现的小鼠谱图重叠，这表明在癌细胞上施加的选择性压力是小鼠和人之间共享的。这些研究证明了跨物种比较的价值，以识别指导构成人类癌症进展的各种细胞过程的功能上重要的驱动基因。在这个为期5年的建议中，我们将从肺腺癌的小鼠模型中生成大规模测序数据集，以识别肿瘤进化过程中获得的点突变。我们将进行跨物种比较研究和途径分析，以对最感兴趣的候选基因和途径进行排名，并精确地表征了这些改变的功能作用，使用基因工程的小鼠模型和人类癌细胞。我们的初步数据表明，这种方法是可行的。我们已经产生了一个由高级，高级鼠肿瘤，细胞系和转移酶组成的鼠肺腺癌组织库，并开发了一种基于杂交的富集平台，用于捕获和测序与癌症相关的基因。使用这种新技术，我们对鼠肺腺癌细胞系进行了测序，并鉴定出在肿瘤进展过程中获得的体细胞突变。