Transposon-insertional Mutagenesis to Decipher Osteosarcomagenesis

描述（由申请人提供）：本K 08职业发展奖（CDA）申请详细说明了在肉瘤生物学领域应用发育遗传学工具的独立临床医生-研究者的发展计划。候选人最近完成了严格的骨科手术和肌肉骨骼肿瘤学的临床培训，在此期间，对科学的渴望一直被搁置。尽管如此，候选人已经表现出持续的愿望，参与科学开始在中学教育，并最终在一个独特的条件敲除小鼠在他的业余时间在手术训练中的一代。现在开始学术任命为外科医生，科学家在一个忙碌繁忙的临床中心儿科肉瘤治疗和研究指导下，最近的诺贝尔奖获得者在儿科肉瘤小鼠模型的研究具有丰富的经验，候选人准备接受密集的准备研究学术生涯。在获得从以患者为导向的研究到小鼠发育遗传模型的假设的反向翻译方面的专业知识后，预计候选人的职业工作不仅将深入了解儿科肉瘤-特别是骨肉瘤-的发病机制及其治疗的改进，而且还将为未来的整形外科医生科学家扩展目前微小的示范模型库。 骨肉瘤是青少年和年轻人癌症死亡的主要原因。此外，它在遗传复杂的非平衡易位型癌症中具有最年轻的发病年龄之一，使其可能具有模式化的发病机制，并可能为理解一般的遗传复杂癌症提供有用的窗口。骨肉瘤发病机制研究的一个主要挑战是没有良性、低度甚至中度的前体病变被识别。在人类肿瘤和小鼠模型中观察到p53和视网膜母细胞瘤易感蛋白（pRb）升高是骨肉瘤发生的关键基因破坏。在不同的成骨细胞前体分化状态和不同的小鼠宿主发育阶段，这些基因的条件性破坏将表征成骨细胞comagenesis的机会窗口。转座子介导的诱变与pRb和p53条件破坏将确定合作基因破坏和扩增所需的完成骨肉瘤的发生，并获得转移表型。 公共卫生相关性：模型骨科外科医生科学家的发展是至关重要的，未来吸引那些有科学抱负的骨科领域，其中包括一些最常见的，最致残的，最不了解的医学问题的护理。骨肉瘤仍然是一种在年轻人群中不可接受的致命和致残性癌症，因此需要提高对骨肉瘤的认识。此外，骨肉瘤是其他遗传复杂癌症的模型，其中许多是主要的公共卫生负担。

DESCRIPTION (provided by applicant): This K08 Career Development Award (CDA) application details the plan for development of an independent clinician-investigator skilled in the application of developmental genetics tools in the area of sarcoma biology. The candidate has recently completed rigorous clinical training in orthopaedic surgery and musculoskeletal oncology, during which aspirations toward science have been on hold. The candidate has nonetheless demonstrated sustained desire for involvement in science beginning during secondary education and culminating in the generation of a unique conditional knock-out mouse in his spare time in the midst of surgical training. Now beginning an academic appointment as a surgeon-scientist in a busy clinical center for pediatric sarcoma treatment and under the research mentorship of a recent Nobel Laureate with extensive experience in the study of pediatric sarcoma mouse models, the candidate is poised to receive intensive preparation for an investigative academic career. After gaining expertise in the reverse translation of hypotheses generated from patient-oriented research to developmental genetic models in mice, it is anticipated that the candidate's career work will not only provide insight into the pathogenesis of pediatric sarcomas-specifically osteosarcoma-and improvements in their treatment, but also expand the currently tiny pool of exemplary models for future would- be orthopaedic surgeon-scientists. Osteosarcoma is a leading cause of cancer death among adolescents and young adults. Further, it has one of the youngest ages of onset among genetically complex non-balanced-translocation-type cancers, making it likely to have patterned pathogenesis and likely to provide a useful window into the understanding of genetically complex cancers in general. A major challenge in the study of the pathogenesis of osteosarcoma is that no benign, low-grade, or even intermediate-grade precursor lesions are recognized. Observations in human tumors and mouse models have elevated p53 and the retinoblastoma susceptibility protein (pRb) as critical gene disruptions for osteosarcomagenesis. Conditional disruption of these genes at varied osteoblast precursor differentiation states and varied mouse host developmental stages will characterize the window of opportunity for osteosarcomagenesis. Transposon-mediated mutagenesis in association with pRb and p53 conditional disruption will identify the cooperative gene disruptions and amplifications needed to complete osteosarcomagenesis and attain the metastatic phenotype. PUBLIC HEALTH RELEVANCE: The development of model orthopaedic surgeon-scientists is crucial to the future attraction of those with scientific aspirations to the field of orthopaedics, which includes care for some of the most frequent, most disabling, and least understood problems in medicine. Improved understanding of osteosarcoma is needed as this remains an unacceptably deadly and disabling cancer in a young population. Further, osteosarcoma is a model for other genetically-complex cancers, many of which are major public health burdens.