Role of p38 MAPK in HSC Self-Renewal and Radiation-Induced Bone Marrow Injury

说明(由申请人提供)：在核恐怖主义风险或辐射事故情况日益增加的背景下，开发针对辐射的新的医学对策至关重要。在这种情况下，受害者可能会受到中等剂量的辐射，这将显著增加因辐射引起的骨髓(BM)损伤而死亡的风险。尤其是当IR剂量大于3Gy时，IR可严重损伤造血干细胞(HSCs)，削弱其自我更新能力，最终导致骨髓衰竭和机体死亡。由于HSC的严重损伤是中、高剂量(3-10GyIR)照射后的主要威胁生命的损伤，保护HSC的自我更新应成为救命抗辐射治疗的主要目标。本实验室等人最近的研究表明，p38激活的蛋白激酶(P38)是HSC自我更新的负性调节因子，其激活可能介导了IR诱导的HSC损伤和骨髓抑制。因此，我们计划阐明p38介导IR诱导的HSC自我更新损伤的细胞和分子机制，并确定p38是否可以作为干预的分子靶点，以减少IR诱导的BM损伤和全身照射(TBI)后的死亡。此外，我们将确定p38抑制是否可以用于促进HSC的体外扩增，因为我们初步研究的数据表明，在HSC体外扩增过程中，p38的激活可以负向调节HSC的自我更新增殖。这将使干细胞移植成为IR后抢救治疗的一种更可行的方法。我们预计，本申请中提出的研究将提供全新的方法来开发新的基于机制的治疗策略，以减轻或治疗IR诱导的骨髓损伤，从而显著提高辐射事故或核恐怖主义受害者的生存和生活质量。核恐怖袭击是美国日益严重的威胁，由于辐射引起的正常组织损伤，特别是对骨髓和造血干细胞的破坏，可造成重大伤亡。该项目的目标是研究一种名为p38的蛋白质在介导辐射诱导的HSC损伤和抑制BM中的作用，这将使我们能够开发基于机制的新疗法，以减少辐射诱导的BM损伤，在核事件中拯救生命，并提高核受害者的长期存活率。

DESCRIPTION (provided by applicant): Development of novel medical countermeasures against radiation is of foremost importance in the context of growing risk of nuclear terrorism or radiation accident scenarios. Under these circumstances, the victims could receive moderate radiation doses that will significantly increase the risk of death due to radiation induced bone marrow (BM) injury. Particularly, if the dose of IR is greater than 3 Gy, IR can severely damage hematopoietic stem cells (HSCs) and impair their ability to self-renew, which could ultimately lead to BM failure and organism death. Since severe damage to HSCs is the primary life-threatening injury after exposure to a moderate or high dose of IR (3-10 Gy), protecting HSC self-renewal should be a main goal in the development of life saving anti-radiation therapies. Recent studies from our laboratory and others suggest that p38 0-activated protein kinase (p38) is a negative regulator of HSC self- renewal and its activation may mediate IR-induced HSC injury and BM suppression. Therefore, we plan to elucidate the cellular and molecular mechanisms by which p38 mediates IR-induced impairment of HSC self-renewal and to determine whether p38 can be molecularly targeted for intervention to reduce IR-induced BM injury and lethality after total body irradiation (TBI) in a mouse model. In addition, we will determine if p38 inhibition can be used to promote ex vivo HSC expansion because the data presented in our preliminary studies suggest that activation of p38 can negatively regulate HSC self- renewal proliferation during ex vivo HSC expansion. This would allow HSC transplantation to be a more viable approach for post IR rescue therapy. We anticipate that the research proposed in this application will offer fundamentally new approaches to develop novel mechanism-based therapeutic strategies to mitigate or treat IR-induced BM injury, which could significantly improve the survival and quality of the life of radiation accident or nuclear terrorism victims. Nuclear terrorist attack, an increasing threat in the United States, can cause significant casualties due to radiation-induced normal tissue damage, particularly damage to the bone marrow (BM) and hematopoietic stem cells (HSCs). The goal of this project is to investigate the role of a protein called p38 in mediating radiation-induced HSC injury and BM suppression, which will allow us to develop novel and mechanism- based therapies to reduce radiation-induced BM damage to save lives in a nuclear event and to increase long-term survival of the nuclear victims.