Age-Related Differences in Response to Radiation and Medical Countermeasures

对辐射和医疗对策的反应与年龄相关的差异

• 批准号: 9203459
• 负责人: CHRISTIE M Orschell
• 金额: $ 5.21万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-23 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9203459
• 关键词: Adult; Affect; Age; Aging; Animal Model; Animals; Biology of Aging; Blood; Blood Platelets; Bone Marrow Purging; Cell Death; Cell physiology; Cells; Cessation of life; Chronic; Ciprofloxacin; Collaborations; DNA Damage; DNA Repair; Data; Department of Defense; Dinoprostone; Elderly; Eligibility Determination; Environment; Event; FDA approved; Failure; Filgrastim; Funding; Gender; Genomic Instability; Grant; Granulocyte Colony-Stimulating Factor; Hematologist; Hematopoiesis; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; Hemorrhage; Homeostasis; Human; Inflammatory; Injury; Institutes; Intervention; Late Radiation Injury; Lisinopril; Maintenance; Medical; Megakaryocytes; Modeling; Mus; Opportunistic Infections; Organ; Organism; Osteoblasts; Outcome; Pathology; Pathway interactions; Patients; Pegfilgrastim; Pharmaceutical Preparations; Physiology; Population; Positioning Attribute; Process; Publishing; Qualifying; Radiation; Radiation Accidents; Radiation Tolerance; Radiation Toxicity; Radio; Radiobiology; Recording of previous events; Recovery; Recovery of Function; Research Personnel; Risk Factors; Signal Transduction; Stem cells; Stress; Stromal Cells; Testing; Tissues; Transplantation; Triad Acrylic Resin; age related; aged; animal rule; base; chemotherapy; cost; drug development; drug sensitivity; efficacy testing; experience; human disease; innovation; juvenile animal; mature animal; meetings; mouse model; named group; neutrophil; normal aging; novel; programs; radiation effect; radiation response; regenerative; response; stem; stem cell biology; stem cell niche; therapy outcome; young adult

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.

相关的和预测性的动物模型对于研究人类疾病和对疾病的反应是重要的。 疗法仅采用幼龄动物的模型可能不能代表老年/老龄动物的反应。 人类种群。涉及辐射的恐怖事件的威胁日益增加， 辐射事故，强调需要有效的医疗对策（MCM）对辐射。 由于动物老化的高成本，老年人群中的动物模型缺乏。它正在成为 造血系统急性放射综合征（H-ARS）模型在幼龄成年动物中日益清晰 并不能充分代表老年人口，因为老年动物（和人类）可能会作出反应， 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， 应答衰老的一般原因被假设是由于进行性慢性 细胞损伤的积累和维持体内平衡和再生能力的降低 潜力 这项提案汇集了独特的合格的调查人员，他们已经合作了几年， 辐射对造血和衰老的影响，目前的资金用于评估辐射和衰老 生物学Orschell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新的 H-ARS的小鼠模型，现在已经开发出老年H-ARS模型。佩鲁斯医生是 在干细胞生物学和压力对造血干细胞的影响的领导者。PI带来了免费的专业知识 在放射生物学，干细胞生物学，衰老，以及新的和发达的成年人和老年人的动物模型， H-ARS拥有最先进的实验平台。 PI将检验高龄影响实验结果和治疗反应的假设， H-ARS动物模型。PI记录了年龄和性别相关的差异， 年轻和老年小鼠的辐射，并缺乏疗效的老年小鼠的唯一一类的MCM迄今 用于治疗H-ARS。他们将在这些发现的基础上，用不同的方法研究MCM。 作用机制，即dmPGE 2、赖诺普利和环丙沙星。在目标2中，造血参数 将在H-ARS模型中对恢复进行动力学研究，特别是：造血细胞的变化 干/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、细胞群和功能差异。 年轻人和老年人对辐射照射的反应之间的差异， 对MCM的反应，以及确定可能提高所有年龄段受害者疗效的目标，特别是 老人该团队处于独特的地位，以评估年龄对结果的影响， 疗法