Genetic Determinants of Radiation induced Hematologic Toxicity

摘要 循环中淋巴细胞的耗尽，血液毒性，是多模式癌症的常见伴随。 心理治疗。淋巴细胞是造血系统中对辐射最敏感的细胞。辐射诱发 循环淋巴细胞计数的耗尽对许多固体患者的总体生存结果有重大影响 癌症。这表明免疫系统在提高辐射疗效方面起着重要作用。 心理治疗。了解放射治疗引起的血液毒性的原因将有助于 预测、预防和改善这一现象并潜在地改善患者结局的新策略。 利用小鼠作为免疫学研究的模式生物，在我们的 了解人类免疫激活和调节的机制，以及 监管失调。然而，大多数老鼠研究使用遗传多样性有限的近交系，并没有反映 在人类身上观察到的不同反应。协作十字(CC)旨在克服这些问题 在受控和可重复的情况下对人类种群中发现的遗传多样性进行建模的局限性 举止。使用CC鼠标资源，我们在983中收集了急性和持续辐射敏感性数据 CC小鼠共17个品系。我们的初步QTL分析确定了几个与 辐射敏感度。一个与急性辐射敏感性相关的小但极显著的QTL 淋巴细胞、B细胞和T细胞位于1号染色体远端，仅包含Ush2A基因 这有力地表明，该基因的变异导致了辐射敏感性。了解基因 影响免疫系统细胞和治疗相关的血液毒性是开发新技术的第一步 根据个体的基因构成进行个性化的治疗。 在这项建议中，我们将通过扩大我们的 现有的辐射引起的血液学毒性数据与另外13株CC菌株一起设置。在目标1中，我们将测试 遗传变异和性别显著影响特定淋巴细胞辐射敏感性的假说 人口和血液参数。在目标2中，我们将测试在我们的初步QTL中确定的Ush2a的作用 分析CC小鼠在辐射暴露后的血液学毒性。基因的鉴定 在我们的小鼠队列中与辐射敏感性相关的标记将导致对 放射治疗引起的淋巴细胞减少，这可能有助于设计新的治疗方法来对抗这种影响。 协同交叉免疫表型和辐射反应数据资源将成为一个有价值的工具 面向广大研究社区，并将允许在多种复杂表型之间进行关联分析 阐述免疫系统对健康和疾病的贡献。

SUMMARY Depletion of circulating lymphocytes, hematologic toxicity, is a common accompaniment of multimodal cancer therapy. Lymphocytes are the most radiosensitive cells of the hematopoietic system. Radiation-induced depletion of circulating lymphocyte counts have a significant impact on overall survival outcomes for many solid cancers. This suggests that the immune system plays an important role in improving the efficacy of radiation therapy. Understanding the causes of radiotherapy induced hematologic toxicity will allow the development of novel strategies to predict, prevent and ameliorate this phenomenon and potentially improve patient outcome. The use of mice as model organisms for immunology research has led to significant advances in our understanding of the mechanisms governing human immune activation and regulation, as well as dysregulation. However, most mice studies use inbred strains with limited genetic diversity and do not reflect the diverse responses observed in humans. The Collaborative Cross (CC) was designed to overcome these limitations by modeling the genetic diversity found in the human population in a controlled and reproducible manner. Using the CC mouse resource, we have collected acute and persistent radiation sensitivity data in 983 CC mice covering 17 CC strains. Our preliminary QTL analysis identified several genetic loci associated with radiation sensitivity. One small, but highly significant QTL associated with acute radiation sensitivity of lymphocytes, B- and T-cells was located on distal chromosome 1 and encompassed only the Ush2A gene strongly suggesting that variations in this gene contribute to radiation sensitivity. Understanding the genes affecting immune system cells and treatment associated hematologic toxicity is the first step in developing novel therapies that are personalized according to an individual’s genetic make-up. In this proposal we will increase power of genetic detection of radiation sensitivity QTL, by expanding our existing radiation induced hematologic toxicity data set with an additional 13 CC strains. In aim 1 we will test the hypothesis that genetic variation and sex significantly influence radiation sensitivity of specific lymphocyte populations and blood parameters. In aim 2, we will test the role of Ush2a, identified in our preliminary QTL analysis in CC mice, in contributing to hematologic toxicity after radiation exposure. The identification of genetic markers associated with radiation sensitivity in our mouse cohort will result in a greater understanding of radiotherapy-induced lymphopenia, which may help design new therapeutic approaches to counter the effect. The Collaborative Cross immunophenotypic and radiation response data resource will become a valuable tool for the broad research community and will allow for association analysis among multiple complex phenotypes to address the contribution of the immune system in health and disease.