Impact of Radiation on Stem Cell Maintenance and Leukemogenesis

辐射对干细胞维持和白血病发生的影响

• 批准号: 8701252
• 负责人: Courtney Jo Fleenor
• 金额: $ 1.88万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-15 至 2015-02-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8701252
• 关键词: Biological; Biological Assay; Bone Marrow Transplantation; Breast; Cancer Etiology; Cancer Model; Cell Culture Techniques; Cell Maintenance; Cell physiology; Cells; Defect; Development; Dose; Erythrocytes; Exposure to; Foundations; Generations; Genes; Genotype; Goals; Gray unit of radiation dose; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Human; Incidence; Individual; Ionizing radiation; Light; Link; Longitudinal Studies; Lung; Maintenance; Malignant Neoplasms; Malignant neoplasm of thyroid; Measures; Mediating; Mission; Modeling; Mus; Mutation; National Cancer Institute; Nutrient; Oncogenes; Oncogenic; Population; Population Dynamics; Radiation; Radiation-Induced Cancer; Relative (related person); Research; Research Proposals; Research Training; Science; Signal Transduction; Skin; Skin Cancer; Stem cells; Testing; Thyroid Gland; Tissues; Tumor Suppression; Tumor Suppressor Proteins; Whole-Body Irradiation; anticancer research; base; cancer prevention; cancer risk; cancer therapy; carcinogenesis; cell injury; fitness; in vivo; irradiation; leukemia; leukemogenesis; malignant breast neoplasm; malignant stomach neoplasm; mutant; neuronal cell body; notch protein; pressure; prevent; self-renewal; stem cell population; trait; treatment strategy; tumorigenesis

DESCRIPTION (provided by applicant): Ionizing radiation (IR) exposure has been associated with increased rate of cancer incidence for over 100 years, but the mechanism underlying this relationship remains poorly understood. IR-induced cancers include lung, skin, thyroid, breast, stomach cancers, and most commonly, leukemias. Long-term studies following humans exposed to large doses of radiation indicate decreased cellular function up to 50 years after the initial exposure, most notably in the hematopoietic compartment. IR-induced carcinogenesis is conventionally attributed to the direct generation of oncogenic mutations. However, our lab has developed an evolutionary based model for cancer development, Adaptive Oncogenesis. Essentially, young, healthy cells maintain high tissue fitness and prevent expansion of oncogenically-initiated cells by outcompeting damaged and mutant cells for nutrients and room. Damage to the entire cellular population, such as after total-body irradiation, decreases the fitness of the population, thereby increasing selective pressure for adaptive oncogenic mutations. Competitive bone marrow transplants, along with ex vivo HSC cultures, indicate that IR exposure causes stable defects in HSC maintenance that can be reversed by activation of Notch1 signaling. The goal of this research proposal is two-fold. 1. To identify the mechanism by which previous IR decreases HSC maintenance; 2. To explore how impaired HSC fitness impacts selection for adaptive oncogenes and leukemogenesis. The research proposal emphasizes a basic biological understanding of hematopoietic fitness maintenance and the foundations of IR-induced carcinogenesis, with potential implications in cancer prevention. The proposed research will help the National Cancer Institute fulfill their mission to support cancer research and training in the fundamental sciences.

描述（由申请人提供）： 100 多年来，电离辐射 (IR) 暴露与癌症发病率增加有关，但人们对这种关系背后的机制仍知之甚少。红外线诱发的癌症包括肺癌、皮肤癌、甲状腺癌、乳腺癌、胃癌，以及最常见的白血病。对人类暴露于大剂量辐射的长期研究表明，在初次暴露后长达 50 年内，细胞功能都会下降，尤其是造血室。 IR诱导的致癌作用通常归因于致癌突变的直接产生。然而，我们的实验室开发了一种基于进化的癌症发展模型，即适应性肿瘤发生。从本质上讲，年轻、健康的细胞保持较高的组织适应性，并通过与受损和突变的细胞竞争营养和空间来防止致癌细胞的扩张。对整个细胞群的损伤，例如全身照射后，会降低细胞群的适应性，从而增加适应性致癌突变的选择压力。竞争性骨髓移植以及离体 HSC 培养表明，IR 暴露会导致 HSC 维持的稳定缺陷，而这种缺陷可以通过激活 Notch1 信号传导来逆转。这项研究计划的目标有两个。 1. 确定既往 IR 降低 HSC 维持的机制； 2. 探讨 HSC 适应性受损如何影响适应性癌基因和白血病发生的选择。该研究提案强调了对造血健康维持的基本生物学理解和红外线诱导致癌的基础，对癌症预防具有潜在影响。拟议的研究将帮助国家癌症研究所履行其支持癌症研究和基础科学培训的使命。