Genetic Determinants of Radiation induced Hematologic Toxicity

总结 循环淋巴细胞的耗竭，血液学毒性，是多模式癌症的常见伴随物 疗法淋巴细胞是造血系统中对辐射最敏感的细胞。辐射诱导 循环淋巴细胞计数的耗竭对许多实体瘤的总体生存结局有显著影响。 癌的这表明免疫系统在提高放射治疗的疗效中起着重要作用 疗法了解放射治疗引起的血液学毒性的原因将有助于发展 预测、预防和改善这种现象并潜在地改善患者结果的新策略。 使用小鼠作为免疫学研究的模式生物，已经在我们的免疫学研究中取得了重大进展。 了解人类免疫激活和调节的机制，以及 失调然而，大多数小鼠研究使用遗传多样性有限的近交系， 在人类身上观察到的不同反应。协作十字架（CC）旨在克服这些问题 通过在受控和可重复的环境中对人类群体中发现的遗传多样性进行建模， 方式使用CC小鼠资源，我们收集了983只小鼠的急性和持续辐射敏感性数据， CC小鼠，覆盖17个CC品系。我们初步的QTL分析确定了几个与 辐射敏感性一个小的，但高度显着的QTL与急性辐射敏感性， 淋巴细胞、B细胞和T细胞位于远端1号染色体上，仅包含Ush 2A基因 这强烈地表明该基因的变异有助于辐射敏感性。了解基因 影响免疫系统细胞和治疗相关的血液学毒性是开发新的 根据个人的基因组成进行个性化治疗。 在这个提议中，我们将通过扩大我们的研究范围， 现有的辐射诱导血液学毒性数据集，另外13个CC菌株。在目标1中，我们将测试 遗传变异和性别显著影响特异性淋巴细胞辐射敏感性假说 人群和血液参数。在目标2中，我们将测试初步QTL中鉴定的Ush2a的作用 在CC小鼠中的分析，在辐射暴露后促成血液学毒性。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物将使我们更好地理解 放射治疗引起的淋巴细胞减少症，这可能有助于设计新的治疗方法来对抗这种影响。 协作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 为广泛的研究界，并将允许多个复杂的表型之间的关联分析， 解决免疫系统在健康和疾病中的作用。

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.