Accidental or intended radiation exposure in a mass casualty setting presents a serious and ongoing threat. While radioprotective agents can be used with some success when given prior to radiation exposure they are of limited use when used post-exposure. The current proposal prepares the groundwork for a post radiation strategy to protect critical tissues affected by ARS within days after the radiation event has occurred. This approach is based on strong preliminary evidence that stromal/stem cell transplantation provides an effective measure to ameliorate radiation injury. Unlike BMT, the critical difference between the two cell transplantation approaches is that endothelial or mesenchymal stem cell transplantation mediates the recovery of damaged host stem cells via accelerated hematopoiesis or intestinal regeneration or wound healing rather than its replacement with donor derived cells. This provides a novel approach to identify the cellular and molecular mechanisms responsible for radiation mitigation. The ultimate goal of this proposal is to exploit this experimental system to identify the factors and signals elaborated by the stromal cells in the stem cell niche (endothelial, mesenchymal and macrophages) that mediate the regeneration of the irradiated gastrointestinal, hematopoietic or cutaneous system. All four projects of this CMCR are thematically based on this premise and have the following objectives: Define pathophysiologic mechanisms, discovery and validation of molecular targets in ARS , Determine how to accelerate stem cell recovery and regeneration by systemic administration of growth factors in mice, Examine whether repair of the ISC niche by TLR activation and/or stromal cell-based therapies could mitigate ARS in vertebrates (i.e. mice and zebrafish), and Explore the potential of modulators of signal transduction to substitute and amplify signals necessary for stem cell survival and regeneration. Project 1: Stem cell-based therapies for mitigation of radiation-induced gastrointestinal syndrome (RIGS). Project 2: Endothelial cell-derived factors for mitigation of bone marrow syndrome. Project 3: Nanoparticle-based therapies for cutaneous radiation syndrome and Project 4: Mitigation of radiation damage by modulating inflammatory signaling pathways.
The CMCR offers many deliverables, such as, intestinal stem cell growth factor, R-spondin1, TLR agonists, GSK inhibitors, Nanoparticle-NO topical agent for wound healing, and endothelial growth factors for mitigation of ARS. Cell based therapies raise hope as transplantation of bone marrow stromal cells mitigate RIGS, 24 hrs after exposure to 18 Gy whole abdominal irradiation.
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