Pleitrophin as a Mitigator of Radiation Induced Hematopoietic Syndrome

造血衰竭是急性放射病的主要死亡原因。不幸的是，很少有人 现有的治疗方法可以有效地减轻辐射对造血系统的损害。 我们假设骨髓微环境中的细胞，特别是内皮细胞 (ECS)，调节辐射损伤后的造血再生。我们最近的研究证实了这一点 这一假说表明，人的内皮细胞在体外产生可诱导人造血干细胞(HSCs)扩增的可溶性蛋白质，而单独移植内皮细胞可将动物从致命的辐射中拯救出来，并加速体内的造血重建。基因筛查显示，多营养素(PTN)是一种肝素结合生长因子，在具有HSC支持活性的内皮细胞中过度表达25倍。我们的初步研究表明，PTN治疗诱导培养的小鼠HSCs扩增10倍，全身给予PTN照射的小鼠表明，与GCSF或生理盐水处理的对照组相比，PTN治疗显著加速了BM HSCs和祖细胞的重建。我们假设PTN在体外和体内调节BM HSCs的自我更新和再生，并且PTN是一种很好的辐射诱导的造血衰竭的候选缓释剂。为了验证我们的假设，我们提出了以下具体目标：1)确定PTN在调节HSC自我更新和动态平衡中的作用。2)确定PTN是否能减轻体内放射性骨髓抑制；3)检测PTN对辐射损伤所致的人造血细胞毒性的影响。我们在这项提案中的广泛目标是提供一种可翻译的、有效的放射诱导的造血损伤缓解剂。我们的初步结果表明，PTN是一种对小鼠和人HSCs可溶的生长因子，与GCSF处理的小鼠相比，PTN全身给药1周可诱导BM HSCs和祖细胞在体内加速再生。PTN具有缓解放射性造血综合征的治疗潜力。

Hematopoietic failure is the major cause of death in Acute Radiation Sickness. Unfortunately, few therapies exist that are effective at mitigating radiation-induced damage to the hematopoietic system. We hypothesized that cells within the bone marrow microenvironment, specifically endothelial cells (ECs), regulate hematopoietic regeneration following radiation injury. Our recent studies validated this hypothesis, demonstrating that human ECs produce soluble proteins that induce the expansion of human hematopoietic stem cells (HSCs) in vitro and transplantation of ECs alone rescued animals from lethal radiation exposure and accelerated hematopoietic reconstitution in vivo. A genetic screen revealed pleiotrophin (PTN), a heparin binding growth factor with no known function in hematopoiesis, as 25-fold overexpressed in ECs with HSC-supportive activity. Our preliminary studies demonstrate that treatment with PTN induces a 10-fold expansion of murine HSCs in culture and systemic administration of PTN to irradiated mice demonstrates that PTN treatment markedly accelerates reconstitution of BM HSCs and progenitor cells compared GCSF- or saline-treated controls. We hypothesize that PTN regulates the selfrenewal and regeneration of BM HSCs in vitro and in vivo and that PTN is an excellent candidate mitigator of radiation-induced hematopoietic failure. In order to test our hypothesis, we propose the following Specific Aims: 1) Determine the function of PTN in regulating HSC self renewal and homeostasis. 2) Determine if PTN can mitigate radiation-induced myelosuppression in vivo, and 3) Test the efficacy of PTN in mitigating human hematopoietic cell toxicity from radiation injury. Our broad objective in this proposal is to deliver a translatable and potent mitigator of radiation-induced hematopoietic injury. Our preliminary results demonstrate that PTN is a soluble growth factor for murine and human HSCs and systemic administration of PTN for 1 week induces the accelerated regeneration of BM HSCs and progenitor cells in vivo compared to GCSF-treated mice. PTN has therapeutic potential as a mitigator of the radiation-induced hematopoietic syndrome.