Skin Stem Cells in Combined Radiation Injury

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DESCRIPTION (provided by applicant): In healthy individuals, exposure to radiation doses as low as 0.5 Gy can lead to detectable changes in circulating lymphocyte counts and doses of 6 Gy can be fatal even with aggressive treatment. Radiation doses of 2 Gy or more can lead to acute radiation syndrome (ARS) but would not be considered life threatening unless that exposure occurred with simultaneous physical trauma or burns. In many terrorist radiation exposure scenarios, injury will likely involve radiation exposure and additional, complicating trauma and or burns. Such combined injuries leads to increased mortality. We hypothesize that radiation acutely modifies the normal wound healing response through damage of local skin stem cells and thus interfering with the host's ability to repair the damaged area. This lack of repair contributes to local chronic inflammatory responses adding to the delayed healing. In order to test this hypothesis, the initial component of this R21 will be to establish the model and the biological monitoring of impact of combined injuries with two specific aims: 1. Define the alterations in the kinetics of wound regeneration following radiation exposure in the MRL mouse and, 2. Define alterations in the molecular and cellular wound regeneration responses following radiation exposure. Once the model is established, we will then proceed in the following years to test the hypothesis and the efficacy of different cellular therapies with the following aims: 1. Determine the effects of radiation on wound healing response of local skin stem cells and transplanted stem cells. 2. Characterize the mechanism through which the transplantation of cellular products accelerates the in vivo recovery from combined radiation injury. We will draw on our broad experience in hematopoietic cell therapy to assess the efficacy of three novel approaches: endothelial progenitors, cord blood cells or mesenchymal stem cell transplantation. These cellular populations have been previously shown to be highly effective in rescuing mice from lethal doses of radiation, primarily through the rescue of the hematopoietic syndrome. In this aim we will assess the direct injection of these cellular fractions into the site of the injured skin as well as intravenous injection. People can tolerate low doses of radiation. However if the radiation is combined with another injury such as a wound, individuals can die. For example, following the bombing of Hiroshima and Nagasaki, or the Chernobyl accident, thermal injury (burns) and trauma concurrent with radiation exposure were a significant medical finding. We hypothesize that radiation acutely modifies the normal wound healing response through damage of local skin stem cells and thus interfering with the host's ability to repair the damaged area. We will test different cell therapies to improve the outcomes in a mouse model.