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

描述（由申请人提供）：在核恐怖主义或辐射事故风险日益增加的背景下，开发新的辐射医疗对策至关重要。在这种情况下，受害者可能会受到中等剂量的辐射，这将大大增加由于辐射引起的骨髓（BM）损伤而死亡的风险。特别地，如果IR的剂量大于3戈伊，IR可严重损伤造血干细胞（HSC）并损害其自我更新的能力，这可最终导致BM衰竭和生物体死亡。由于HSC的严重损伤是暴露于中等或高剂量IR（3-10戈伊）后的主要危及生命的损伤，因此保护HSC自我更新应该是开发挽救生命的抗辐射疗法的主要目标。本实验室和其他研究表明p38 0-活化蛋白激酶（p38）是HSC自我更新的负调节因子，其活化可能介导IR诱导的HSC损伤和BM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是否可以分子靶向干预，以减少全身照射（TBI）后小鼠模型中IR诱导的BM损伤和致死率。此外，我们将确定p38抑制是否可用于促进离体HSC扩增，因为我们的初步研究中提供的数据表明，p38的激活可在离体HSC扩增期间负调节HSC自我更新增殖。这将使HSC移植成为IR后补救治疗的更可行的方法。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BM损伤，这可以显着提高辐射事故或核恐怖主义受害者的生存率和生活质量。核恐怖袭击是美国日益严重的核威胁，它会对人体正常组织，特别是骨髓和造血干细胞造成损伤，从而造成严重的人员伤亡。该项目的目标是研究称为p38的蛋白质在介导辐射诱导的HSC损伤和BM抑制中的作用，这将使我们能够开发新的基于机制的疗法来减少辐射诱导的BM损伤，以在核事件中挽救生命并增加核受害者的长期生存。

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.