Transposon-insertional Mutagenesis to Decipher Osteosarcomagenesis

描述（由申请人提供）：本K08职业发展奖（CDA）申请详细说明了在肉瘤生物学领域中熟练应用发育遗传学工具的独立临床研究者的发展计划。这位候选人最近完成了骨科手术和肌肉骨骼肿瘤学方面的严格临床训练，在此期间，他对科学的渴望一直被搁置。尽管如此，这位候选人从中学教育开始就表现出对科学的持续渴望，并在外科训练期间的业余时间培育出了一只独特的条件敲除小鼠。现在，在一个繁忙的儿科肉瘤治疗临床中心开始作为外科医生和科学家的学术任命，并在一位在儿科肉瘤小鼠模型研究方面具有丰富经验的最近的诺贝尔奖获得者的研究指导下，该候选人准备接受深入的学术研究生涯准备。在将以患者为导向的研究产生的假设反向转化为小鼠发育遗传模型方面获得专业知识后，预计该候选人的职业工作不仅将为儿童肉瘤（特别是骨肉瘤）的发病机制提供见解，并改善其治疗方法，而且还将为未来的骨科外科医生扩大目前微小的示范模型库。

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.