Transposon-insertional Mutagenesis to Decipher Osteosarcomagenesis

描述(由申请人提供)：这份K08职业发展奖(CDA)申请书详细说明了一名独立临床医生-调查员的发展计划，该研究员擅长于在肉瘤生物学领域应用发育遗传学工具。这位候选人最近完成了骨科外科和肌肉骨骼肿瘤学方面的严格临床培训，在此期间，对科学的抱负一直被搁置。尽管如此，这位候选人还是表现出了对参与科学的持续渴望，从中学教育开始，最终在外科培训期间的业余时间产生了一种独特的条件基因敲除小鼠。现在，在一家繁忙的儿科肉瘤治疗临床中心，在最近一位在儿科肉瘤小鼠模型研究方面拥有丰富经验的诺贝尔奖获得者的研究指导下，这位候选人开始了一项学术任命，成为一名外科医生兼科学家，他将为未来的研究学术生涯做好紧张的准备。在获得了将以患者为导向的研究产生的假说反向转换为小鼠发育遗传模型的专业知识后，预计候选人的职业工作不仅将为儿童肉瘤-特别是骨肉瘤-的发病机制提供洞察力，并改进其治疗，还将扩大目前极少的示范模型池，供未来的骨科外科科学家使用。 骨肉瘤是青少年和年轻人癌症死亡的主要原因。此外，在基因复杂的非平衡易位型癌症中，它是发病年龄最小的之一，这使得它可能具有模式化的发病机制，并可能提供一个有用的窗口，让人们从总体上了解基因复杂的癌症。骨肉瘤发病机制研究中的一个主要挑战是没有发现良性、低度、甚至中级的前驱病变。在人类肿瘤和小鼠模型中的观察表明，P53和视网膜母细胞瘤易感蛋白(PRB)作为骨肉瘤形成的关键基因中断而升高。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成为骨肉瘤发生的机会之窗。转座子介导的突变结合pRb和p53的条件破坏将识别完成骨肉瘤形成和获得转移表型所需的协作性基因破坏和扩增。 公共卫生相关性：模范整形外科医生-科学家的发展对于未来吸引那些有科学抱负的人进入整形外科领域至关重要，其中包括护理一些最常见、最致残和最不被理解的医学问题。需要提高对骨肉瘤的了解，因为在年轻人群中，骨肉瘤仍然是一种不可接受的致命和致残性癌症。此外，骨肉瘤是其他基因复杂癌症的模型，其中许多癌症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.