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

剖析电离辐射促进胸腺癌前细胞克隆扩张的机制

• 批准号: 9353350
• 负责人: Chang-Lung Lee
• 金额: $ 11.61万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9353350
• 关键词: Acute; Adverse effects; Animal Model; Area; Award; Biology; Bone Marrow; Bone Marrow Transplantation; Cancer Etiology; Cancer Survivor; Cell Death; Cells; Cellular biology; Chromatin; Clinical; Clonal Expansion; DNA Damage; Data; Development; Early Diagnosis; Epigenetic Process; Exposure to; Fostering; Foundations; Future; Genes; Goals; Grant; Health; Hematologic Neoplasms; Hematopoiesis; Hematopoietic; Human; Immunology; Implant; Ionizing radiation; Knowledge; Lymphoma; Lymphomagenesis; Malignant Neoplasms; Mediating; Medical; Mission; Modeling; Mouse Strains; Mutate; Mutation; Nude Mice; Oncogenic; Population; Premalignant; Premalignant Cell; Prevention; Public Health; Radiation; Radiation therapy; Radiobiology; Regulator Genes; Research; Research Personnel; Research Support; Risk; Risk Assessment; Role; Second Primary Cancers; Second Primary Neoplasms; Study models; T-Lymphocyte; TP53 gene; Testing; Thymic Lymphoma; Thymus Gland; Training; Tumor Suppressor Genes; United States; United States National Institutes of Health; Whole-Body Irradiation; Writing; cancer therapy; carcinogenesis; career development; cell growth; chemotherapy; clinically significant; exome sequencing; improved; in vivo; innovation; insight; irradiation; leadership development; mouse model; novel; novel strategies; pre-clinical; prevent; progenitor; programs; public health relevance; radiation effect; skills; small hairpin RNA; stem; thymocyte; thymus transplantation

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.

项目摘要 由于癌症幸存者数量不断增加，约占人口的4.5％ 美国（2014年），与化学疗法和/或放射疗法有关的第二次恶性肿瘤是重要的 关注公共卫生。但是，第二次恶性肿瘤的潜在机制知之甚少。 虽然众所周知的电离辐射可以在小动物模型中诱导癌症，但辐射是否导致 通过创建突变或通过促进具有预先存在的细胞的扩展来创建突变的第二癌 突变仍然是积极研究的领域。这种知识差距代表了评估评估的重大障碍 第二次恶性肿瘤的风险，并制定预防或减轻这种临床意义的新型策略 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 茎/祖细胞池内的微环境和细胞竞争，以促进第二 血液学恶性肿瘤。为了成功启动我的独立研究计划，研究了这个问题， 我将使用此K99/R00奖项来实现我的短期目标，以提高造血和造血专业知识 胸腺波西斯，2）获得研究开始和进展的表观遗传变化的知识和技能集 辐射引起的胸腺淋巴瘤和3）接受赠款写作，领导和职业的重点培训 发展。这三个目标代表了持续发展对我至关重要的领域 成功过渡到独立研究者。拟议的研究具有创新性，因为它挑战了 传统的观点认为辐射主要通过创建新的突变引起癌症。相反，这个 提案检验了以前存在突变的辐射促进细胞生长的假设。这 拟议的研究很重要，因为它将为辐射的非靶向作用提供一种机制 诱导的致癌作用，在60多年的时间内尚未理解。最终，概念 拟议的研究使进步成为可能，将使对鼠标模型有更多的完整了解 辐射诱导的胸腺淋巴瘤，并建立了评估新医学的临床前平台 反对辐射引起的血液系统恶性肿瘤的对策。