The overall goal of this proposal is to develop a novel therapy - prostaglandin E2 (PGE2) - to mitigate the effects of radiation on the hematopoietic system. This robust cellular system is disrupted and damaged by exposure to radiation, which results in cytopenias leading to life-threatening infections, anemia, and bleeding. The onset and extent of platelet loss predicts survival following total body irradiation. The majority of agents that have been developed and stockpiled for use as part of a radiological emergency are specifically targeted at the clinical consequences of white blood cell loss. Although much work has been done over the past decades, few agents have transitioned from bench to clinic. The collaborative studies of the Palis and Calvi labs within the University of Rochester's Center for Medical Countermeasures against Radiation have resulted in the development of robust mouse models of acute and late radiation injury. Our preliminary studies indicate that PGE2, delivered 48-72 hours after acute radiation exposure, mitigates the megakaryocyte lineage leading to more rapid platelet recovery. In addition, PGE2 acutely mitigates the number of phenotypic HSC. We hypothesize that PGE2 acts through the marrow microenvironment, specifically at the level of endothelial cells and macrophage populations, to mitigate radiation-induced injury of hematopoietic stem cells and megakaryocyte precursors. We will assess the effectiveness and mechanism of PGE2 mitigation of acute and late hematologic injury. Our joint studies have also identified a special population - 14 day old mice - as being particularly sensitive to relatively lw sublethal radiation exposure, since they develop not only a severe reduction in phenotypic HSCs but also late peripheral cytopenias. A better understanding of the differential response between pediatric and adult populations, both to radiation injury and any proposed agents, will be required to develop treatments with broad applicability. We will, therefore, also investigate the efficacy of PGE2 to mitigate late injury to the hematopoietic system of pediatric versus adult populations. Taken together, our proposed collaborative, mechanistic studies will bring forward PGE2, a promising new agent with an established safety profile, for use in mitigating both acute and late effects of radiation exposure.
The blood system is remarkably sensitive to radiation injury, resulting in life-threatening infections, anemia, and bleeding. The overall goal of this research i to investigate the efficacy and mechanism of action of Prostaglandin E2 to mitigate the effects of radiation on platelet production and blood stem cell numbers in the bone marrow. We have also established that radiation causes more damage to the blood system of childhood versus adult mice and will study the efficacy of Prostaglandin E2 to mitigate radiation injury in this special pediatric population.
|Latchney, Sarah E; Calvi, Laura M (2017) The aging hematopoietic stem cell niche: Phenotypic and functional changes and mechanisms that contribute to hematopoietic aging. Semin Hematol 54:25-32|
|Li, Allison J; Calvi, Laura M (2017) The microenvironment in myelodysplastic syndromes: Niche-mediated disease initiation and progression. Exp Hematol 55:3-18|
|Lawal, Rialnat A; Zhou, Xichao; Batey, Kaylind et al. (2017) The Notch Ligand Jagged1 Regulates the Osteoblastic Lineage by Maintaining the Osteoprogenitor Pool. J Bone Miner Res 32:1320-1331|
|Evans, Andrew G; Calvi, Laura M (2015) Notch signaling in the malignant bone marrow microenvironment: implications for a niche-based model of oncogenesis. Ann N Y Acad Sci 1335:63-77|
|McGrath, Kathleen E (2015) Utilization of imaging flow cytometry to define intermediates of megakaryopoiesis in vivo and in vitro. J Immunol Methods 423:45-51|
|Frisch, Benjamin J; Calvi, Laura M (2014) Hematopoietic stem cell cultures and assays. Methods Mol Biol 1130:315-324|
|Frisch, Benjamin J; Calvi, Laura M (2014) Osteoblasts as leukemia-initiating cells. Bonekey Rep 3:572|
|Balderman, Sophia R; Calvi, Laura M (2014) Biology of BM failure syndromes: role of microenvironment and niches. Hematology Am Soc Hematol Educ Program 2014:71-6|
|Calvi, Laura M; Link, Daniel C (2014) Cellular complexity of the bone marrow hematopoietic stem cell niche. Calcif Tissue Int 94:112-24|
|Niswander, Lisa M; Fegan, Katherine H; Kingsley, Paul D et al. (2014) SDF-1 dynamically mediates megakaryocyte niche occupancy and thrombopoiesis at steady state and following radiation injury. Blood 124:277-86|
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