Dissecting mechanism(s) by which ionizing radiation promotes clonal expansion of premalignant cells in the thymus

项目总结 由于癌症幸存者的数量不断增加，约占#年人口的4.5% 美国(2014)，与化疗和/或放射治疗有关的第二种恶性肿瘤是一个重要的 对公共卫生的关注。然而，第二种恶性肿瘤的潜在机制还知之甚少。 虽然众所周知，电离辐射可以在小动物模型中诱发癌症，但辐射是否会导致 第二种癌症是通过产生起始突变或通过促进含有先前存在的 突变仍然是一个活跃的研究领域。这一知识差距是评估 第二种恶性肿瘤的风险，并开发新的策略来预防或减轻这种临床意义上的 癌症治疗的副作用。这项研究的长期目标是研究电离辐射如何改变 干细胞/祖细胞池内的微环境和细胞竞争促进第二代的发育 恶性血液病。为了成功启动我研究这个问题的独立研究项目， 我将利用这个K99/R00奖项来实现我的短期目标：1)发展造血专业知识， 胸腺生成，2)获得知识和技能，研究表观遗传变化在胸腺疾病的发生和发展中的作用 辐射诱发的胸腺淋巴瘤，以及3)接受赠款撰写、领导力和职业生涯方面的重点培训 发展。这三个目标代表了持续发展对我的 成功过渡到独立调查员。这项拟议的研究具有创新性，因为它对 传统观点认为，辐射主要通过产生新的突变而导致癌症。相反，这是 该提议验证了辐射促进具有预先存在的突变的细胞生长的假设。这个 拟议的研究具有重要意义，因为它将为辐射的非靶向影响提供一种机制- 诱导致癌，60多年来人们对此知之甚少。归根结底，概念 拟议中的研究取得的进展将使我们能够更全面地了解老鼠模型 治疗辐射诱发的胸腺淋巴瘤，并为评估新药物建立临床前平台 辐射诱发血液系统恶性肿瘤的防治对策。

PROJECT SUMMARY Due to an ever-increasing number of cancer survivors, representing approximately 4.5% of the population in the United States (2014), second malignancies related to chemotherapy and/or radiotherapy is a significant concern in public health. However, underlying mechanisms of second malignancies are poorly understood. While it is well known ionizing radiation can induce cancers in small animal models, whether radiation causes second cancer by creating initiating mutations or by promoting the expansion of cells that harbor a pre-existing mutation remains a field of active study. This knowledge gap represents a substantial barrier to assessing the risk of second malignancies and to develop novel strategies for preventing or mitigating this clinically significant side effect of cancer therapy. The long-term goal of this research is to study how ionizing radiation alters the microenvironment and cell competition within the stem/progenitor pool to promote the development of second hematological malignancies. To successfully launch my independent research program studying this question, I will use this K99/R00 award to achieve my short-term objectives to 1) develop expertise in hematopoiesis and thymopoiesis, 2) gain knowledge and skill sets studying epigenetic changes in the onset and progression of radiation-induced thymic lymphoma, and 3) receive focused training in grant writing, leadership and career development. These three objectives represent areas where continued development is crucial for my successful transition to an independent investigator. The proposed research is innovative in that it challenges the conventional view that radiation causes cancer predominantly by creating new mutations. Instead, this proposal tests the hypothesis that radiation promotes the growth of cells with preexisting mutations. The proposed research is significant because it will provide a mechanism for non-targeted effects of radiation- induced carcinogenesis, which remains poorly understood for over 60 years. Ultimately, the conceptual advances made possible by the proposed research will enable more complete understanding of mouse models of radiation-induced thymic lymphoma and establish a preclinical platform for evaluating novel medical countermeasures against radiation-induced hematological malignancies.