Age-Related Differences in Response to Radiation and Medical Countermeasures

相关的和可预测的动物模型对于研究人类疾病和应对 心理治疗。只使用幼年动物的模型可能不能代表老年人/老年人的反应 人类人口。涉及辐射的恐怖主义事件的威胁与日俱增，以及 辐射事故，强调了针对辐射的有效医学对策的必要性。 由于老龄动物的高昂成本，老年人口中缺乏动物模型。它正在成为 越来越清楚的是，幼年成年动物的造血型急性辐射综合征(H-ARS)模型 不能很好地代表老龄化的种群，因为年长的动物(和人类)可能会做出反应 由于年龄相关的放射敏感性、器官敏感性、药物敏感性或性别的变化而导致的不同 回应。衰老的一般原因被认为是由渐进性慢性疾病引起的 细胞损伤的积累和维持体内平衡和再生能力的减弱 潜力。 这项提议汇集了几年来合作多年的独特合格的调查人员。 辐射对造血和衰老的影响及目前用于评估放射治疗和衰老的资金 生物学。奥谢尔博士是一位放射生物学家和实验血液学家，他开发并验证了一种 在年轻成年小鼠中建立H-ARS模型，现在已经发展出老年H-ARS模型。佩勒斯博士是一位 在干细胞生物学和压力对血液干细胞的影响方面处于领先地位。私人助理带来了免费的专业知识 在放射生物学、干细胞生物学、衰老以及新的和发展的成人和老年动物模型方面 H-ARS拥有最先进的实验平台。 PIs将测试这一假设，即高龄会影响实验结果和治疗反应 H-ARS动物模型的建立。PIs记录了与年龄和性别相关的差异 幼年和老年小鼠对辐射缺乏疗效，而老年小鼠是迄今为止唯一一类MCM 被批准用于H-ARS的治疗。他们将在这些发现的基础上，用不同的方式调查MCM 作用机制，即dmPGE2、赖诺普利和环丙沙星。在目标2中，造血参数 恢复将在H-ARS模型中进行动力学研究，特别是：造血细胞的变化 干细胞/祖细胞和基质细胞支持群体、DNA修复和细胞死亡/破坏途径。 这些结果将确定与年龄和性别相关的通路(S)、细胞群和功能的差异 年轻人和老年人对辐射暴露的反应可能预测或解释变化 对MCMS的反应，以及确定可能提高所有年龄段受害者的疗效的目标，特别是 老年人。该团队在评估年龄对结果和反应的影响方面具有独特的地位 心理治疗。

Relevant and predictive animal models are important to the study of human disease and response to therapy. Models that employ only young animals may not be representative of the response of older/aged human populations. The growing threat of terrorist events involving radiation, as well as the potential for radiation accidents, underscores the need for effective medical countermeasures (MCM) against radiation. Animal models in the geriatric population are lacking due to the high cost of aging the animals. It is becoming increasingly clear that models of the hematopoietic acute radiation syndrome (H-ARS) in young adult animals are not adequate representations of aged populations, since older animals (and humans) are likely to react differently due to age-related changes in radiosensitivity, organ sensitivities, drug sensitivity, or gender responses. The general causes of aging have been hypothesized to result from the progressive chronic accumulation of cellular damage and the diminished capacity to maintain homeostasis and regenerative potential. This proposal brings together uniquely qualified investigators who have collaborated for several years on radiation effects on hematopoiesis and aging with current funding to evaluate radiomitigation and aging biology. Dr. Orschell is a radiobiologist and experimental hematologist who developed and validated novel murine models of H-ARS in young adult mice and has now developed a geriatric H-ARS model. Dr. Pelus is a leader in stem cell biology and the effects of stress on blood stem cells. The PIs bring complimentary expertise in radiobiology, stem cell biology, aging, as well as novel and developed animal models of adult and geriatric H-ARS with state of the art experimental platforms. The PIs will test the hypothesis that advanced age impacts experimental outcome and response to therapy in animal models of H-ARS. The PIs have documented age- and gender-related differences in the response of young and geriatric mice to radiation, and lack of efficacy in geriatric mice of the only class of MCM thus far approved for treatment of H-ARS. They will build upon these findings and investigate MCM with different mechanisms of action, namely dmPGE2, lisinopril, and ciprofloxacin. In Aim 2, parameters of hematopoietic recovery will be investigated kinetically in the H-ARS model, specifically: changes in hematopoietic stem/progenitor and stromal cell supportive populations, DNA repair, and cell death/destruction pathways. These results will identify age- and gender-related differences in pathway(s), cell populations, and function between young and aged populations in response to radiation exposure that may predict or explain altered responsiveness to MCMs, as well as identify targets that may enhance efficacy in victims of all ages, especially the elderly. The team is uniquely positioned to evaluate the effects of age on outcomes and response to therapy.