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.
The overall aim of this proposal is to evaluate if age is a specific risk factor to experimental outcome and response to therapy in a murine model of H-ARS. We will specifically evaluate MCMs with different mechanism of action and evaluate parameters of hematopoietic recovery that may predict or explain altered responsiveness to MCMs, thereby identifying targets that can be explored to enhance or restore efficacy.
