Transposon-insertional Mutagenesis to Decipher Osteosarcomagenesis

转座子插入突变破译骨肉瘤发生

• 批准号: 7788272
• 负责人: Kevin Bruce Jones
• 金额: $ 17.93万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-28 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7788272
• 关键词: Adolescent; Age of Onset; Animals; Appointment; Area; Benign; Biological Models; Biology; Cancer Etiology; Caring; Cell Differentiation process; Cells; Cellular biology; Cessation of life; Characteristics; Childhood; Clinical; Complex; Development; Development Plans; Disease; Education; Environment; Equilibrium; Event; Foundations; Future; Generations; Genes; Genetic; Genetic Models; Genetic Screening; Histology; Human; Incidence; Insertional Mutagenesis; K-Series Research Career Programs; Knockout Mice; Lesion; Location; Malignant Childhood Neoplasm; Malignant Neoplasms; Mediating; Medicine; Mentorship; Metaphysis; Methods; Modeling; Molecular Profiling; Mus; Musculoskeletal; Mutagenesis; Neoplasm Metastasis; Oncogenic; Operative Surgical Procedures; Orthopedic Surgery procedures; Orthopedics; Osteoblasts; Pathogenesis; Pathway interactions; Pattern; Phenotype; Population; Predisposition; Preparation; Proteins; Public Health; Research; Research Personnel; Retinoblastoma; Science; Scientist; Shadowing (Histology); Site; Source; Staging; Surgeon; TP53 gene; Testing; Time; Training; Translations; Tumor Suppressor Proteins; Work; base; cancer type; career; developmental genetics; experience; improved; insight; long bone; model development; mouse model; oncology; osteoblast differentiation; osteosarcoma; patient oriented research; prospective; public health relevance; sarcoma; tool; trait; tumor; young adult

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.

描述（由申请人提供）：该K08职业发展奖（CDA）申请详细介绍了独立临床医生评估者在Saroma Biology领域应用发育遗传学工具方面的制定计划。该候选人最近在骨科手术和肌肉骨骼肿瘤学方面完成了严格的临床培训，在此期间，对科学的愿望一直搁置。尽管如此，该候选人仍表现出了从中学教育期间开始参与科学的持续渴望，并在外科手术训练中的业余时间达到了一代独特的有条件敲除老鼠的渴望。现在，在繁忙的儿科肉瘤治疗中心，在最近的诺贝尔奖获得者的研究指导下，开始在繁忙的诺贝尔奖获得者的研究指导下，开始担任外科医生科学家的学术任命。 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. 骨肉瘤是青少年和年轻人癌症死亡的主要原因。此外，它具有遗传复杂的非平衡 - 转移型癌症中最年轻的发病年龄之一，使其可能具有模式化的发病机理，并可能为理解一般的遗传复杂癌症提供了有用的窗口。研究骨肉瘤发病机理的一个主要挑战是，尚无良性，低度甚至中级前体病变。人类肿瘤和小鼠模型的观察结果升高p53，视网膜母细胞瘤蛋白（PRB）作为骨共核的关键基因破坏。这些基因在各种成骨细胞前体分化态和各种小鼠宿主发育阶段的条件破坏将表征骨共核的机会窗口。转座子介导的诱变与PRB和p53有条件破坏相关，将确定完成整骨共生作用并获得转移表型所需的合作基因破坏和放大。 公共卫生相关性：骨科医生科学家模型的发展对于对骨科领域有科学愿望的人们的未来吸引至关重要，其中包括护理一些最常见，最常见，最残疾，最不知情的医学问题。需要提高对骨肉瘤的了解，因为这仍然是一种致命的致命，并且在年轻人口中使癌症致命。此外，骨肉瘤是其他遗传复合癌的模型，其中许多是主要的公共卫生负担。