Skin Stem Cells in Combined Radiation Injury

描述(申请人提供)：在健康个体中，暴露在低至0.5GY的辐射剂量下可导致循环淋巴细胞计数的可检测到变化，而6GY的剂量即使在积极治疗的情况下也可能是致命的。2GY或更高的辐射剂量可能会导致急性辐射综合征(ARS)，但不会被认为有生命危险，除非这种暴露与身体创伤或烧伤同时发生。在许多恐怖分子辐射暴露的情况下，伤害可能涉及辐射暴露和额外的、复杂的创伤和/或烧伤。这种复合损伤会导致死亡率增加。我们假设，辐射通过损伤局部皮肤干细胞来剧烈地改变正常的伤口愈合反应，从而干扰宿主修复受损区域的能力。这种缺乏修复的情况会导致局部的慢性炎症反应，增加愈合的延迟。为了验证这一假设，R21的初始组成部分将是建立复合损伤影响的模型和生物监测，具有两个特定的目的：1.确定辐射暴露后MRL小鼠伤口再生动力学的变化；2.确定辐射暴露后分子和细胞创伤再生反应的变化。一旦模型建立，我们将在接下来的几年里继续测试不同细胞疗法的假设和疗效，目的如下：1.确定辐射对局部皮肤干细胞和移植干细胞伤口愈合反应的影响。2.阐明细胞移植促进体内复合辐射损伤恢复的机制。我们将借鉴我们在造血细胞治疗方面的广泛经验，评估三种新方法的有效性：内皮祖细胞、脐带血细胞或间充质干细胞移植。以前已经证明，这些细胞群体在将小鼠从致命剂量的辐射中拯救出来方面非常有效，主要是通过拯救造血综合征。为了达到这个目的，我们将评估将这些细胞部分直接注射到受伤皮肤部位以及静脉注射的方法。人们可以耐受低剂量的辐射。然而，如果辐射与另一种损伤(如伤口)合并，个人可能会死亡。例如，在广岛和长崎原子弹爆炸或切尔诺贝利事故之后，热损伤(烧伤)和伴随辐射暴露的创伤是一个重要的医学发现。我们假设，辐射通过损伤局部皮肤干细胞来剧烈地改变正常的伤口愈合反应，从而干扰宿主修复受损区域的能力。我们将测试不同的细胞疗法，以改善小鼠模型的结果。

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.