Skin Stem Cells in Combined Radiation Injury

描述（由申请人提供）：在健康个体中，暴露于低至0.5 Gy的辐射剂量可导致循环淋巴细胞计数可检测到的变化，而6 Gy的剂量即使在积极治疗下也可能致命。2戈瑞或以上的辐射剂量可导致急性辐射综合征（ARS），但不会被认为危及生命，除非同时发生身体创伤或烧伤。在许多恐怖主义辐射暴露情景中，伤害可能包括辐射暴露和额外的、复杂的创伤和/或烧伤。这种复合伤害导致死亡率增加。我们假设辐射通过局部皮肤干细胞的损伤严重改变了正常的伤口愈合反应，从而干扰了宿主修复受损区域的能力。这种修复的缺乏导致局部慢性炎症反应，增加了愈合的延迟。为了验证这一假设，本R21的初始组成部分将是建立模型并对合并损伤的影响进行生物监测，具体目标有两个：1。定义辐射暴露后MRL小鼠伤口再生动力学的变化；定义辐射暴露后分子和细胞伤口再生反应的变化。一旦模型建立，我们将在接下来的几年中继续测试假设和不同细胞疗法的功效，目的如下：测定辐射对局部皮肤干细胞和移植干细胞创面愈合反应的影响。2. 描述细胞产物移植加速联合辐射损伤体内恢复的机制。我们将利用我们在造血细胞治疗方面的丰富经验来评估三种新方法的疗效：内皮祖细胞、脐带血细胞或间充质干细胞移植。这些细胞群先前已被证明在从致死剂量的辐射中拯救小鼠方面非常有效，主要是通过拯救造血综合征。在这个目的中，我们将评估将这些细胞组分直接注射到受伤皮肤部位以及静脉注射。人们可以忍受低剂量的辐射。然而，如果辐射与其他伤害（如伤口）结合，个体可能会死亡。例如，在轰炸广岛和长崎或切尔诺贝利事故之后，与辐射照射同时发生的热伤（烧伤）和创伤是一个重大的医学发现。我们假设辐射通过局部皮肤干细胞的损伤严重改变了正常的伤口愈合反应，从而干扰了宿主修复受损区域的能力。我们将在小鼠模型中测试不同的细胞疗法以改善结果。

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.