Development of dmPGE2 and Bcl-xl-targeting senolytics as medical countermeasures for H-ARS and DEARE

涉及辐射的恐怖事件的威胁越来越大，以及发生辐射事故的可能性越来越大， 强调需要针对辐射采取有效的医学对策。造血系统 是对辐射最敏感的组织，导致造血急性辐射综合征(H-ARS)后 如果不治疗，高剂量辐射暴露会导致感染和/或出血死亡。H-ARS幸存者受苦 由于晚年受到急性辐射暴露(DEARE)的延迟影响，一些慢性病影响 多个器官系统。迄今为止，Neupogen(粒细胞集落刺激因子，G-CSF)，Neulasta (PEGylated-G-CSF)和Leukine®(GM-CSF)是FDA批准的唯一用于治疗H-ARS的MCM， 并将作为暴露在高剂量辐射下的个人的一线治疗。这项提议带来了 独一无二的合格研究人员与长期富有成效的合作研究1616 H-ARS和DeARE中二甲基前列腺素E_2(DmPGE_2)与造血再生奥谢尔博士是一位 放射生物学家和实验血液学家，他在所有年龄段的小鼠中开发和验证了H-ARS模型 和菌株。佩卢斯博士是造血干细胞生物学和二十烷类生物学领域的领军人物。总而言之，Co- PIS已经表明，在致命性辐射暴露后30小时内单次给予dmPGE2，显著 提高30天存活率和造血功能恢复。与合作者米勒博士一起，研究小组已经证明了 在照射前给予dmPGE2作为辐射防护剂，可显著减轻造血，淋巴， 心脏和肾脏的死亡。然而，dmPGE2和上面列出的三个许可的MCM中的任何一个都显示了 作为放射增强剂给予DeARE的疗效(在照射后)。合作者、Deare专家周博士 和衰老，最近加入了该小组，以测试新型的以Bcl-xl为靶向的衰老药物的能力 减轻用dmPGE2作为放射增强剂治疗的小鼠的DeARE。PI将检验dmPGE2的假设 满足H-ARS的理想MCM的所有要求，当与幸存者的感觉神经降解剂一起使用时， 体现了一项有效的战略，以减轻致命性辐射暴露的急性毒性和延迟毒性。这个 将测试以下具体目标：1)确定最佳给药方案和延迟给药 DmPGE2在成熟的年轻成年、儿童和Jackson多样性近交系小鼠模型中的时间表 B)在灵长类动物中进行dmPGE2的PK，2)建立在以下情况下影响转录的机制 DmPGE2在暴露24小时后作为放射增强剂给药，并识别目标造血细胞 (3)探讨dmPGE2与一种新的非脂类LPA2受体RP-1的结合活性。 激动剂(与Tigyi博士合作)，b)Neupogen®，以及c)一种新的抗衰老MCM(与周博士合作)，以确定联合 与MCM或MCM相比，给药在H-ARS和/或DeARE小鼠模型中具有更好的疗效 单独的。到目前为止，我们的数据与成功完成这项提案的数据相结合，将使dmPGE2 进一步发展成为一种被批准用于造福人类的大规模因果事件的MCM。

The growing threat of terrorist events involving radiation, as well as the potential for radiation accidents, underscores the need for effective medical countermeasures (MCM) against radiation. The blood-forming system is the most sensitive tissue to radiation, resulting in the hematopoietic acute radiation syndrome (H-ARS) after high dose radiation exposure and death from infection and/or bleeding if untreated. Survivors of H-ARS suffer later in life by the delayed effects of acute radiation exposure (DEARE), a number of chronic illnesses affecting multiple organ systems. To date, Neupogen (granulocyte-colony stimulating factor, G-CSF), Neulasta (pegylated-G-CSF), and Leukine® (GM-CSF) are the only MCM approved by the FDA for treatment of H-ARS, and will be given as first-line treatments for individuals exposed to high dose radiation. This proposal brings together uniquely qualified investigators with a long-term productive collaboration studying the efficacy of 16,16 dimethyl prostaglandin E2 (dmPGE2) in H-ARS and DEARE and hematopoietic regeneration. Dr. Orschell is a radiobiologist and experimental hematologist who developed and validated models of H-ARS in mice of all ages and strains. Dr. Pelus is a leader in hematopoietic stem cell biology and eicosanoid biology. Together, the Co- PIs have shown that a single dose of dmPGE2 given up to 30hr after lethal radiation exposure, significantly enhanced 30 day survival and hematopoietic recovery. With collaborator Dr. Miller, the team has shown that dmPGE2 given as a radioprotectant before irradiation provides significant alleviation of hematopoietic, lymphoid, cardiac and renal DEARE. However, dmPGE2, nor any of the three licensed MCM listed above, have shown efficacy for DEARE when given as radiomitigators (after irradiation). Collaborator Dr. Zhou, an expert in DEARE and senescence, has recently joined the group to test the ability of novel Bcl-xl-targeting senolytic agents to alleviate DEARE in mice treated with dmPGE2 as a radiomitigator. The PIs will test the hypothesis that dmPGE2 fulfills all the requirements of an ideal MCM for H-ARS and when used in conjunction with senolytics in survivors, embodies an effective strategy to mitigate both the acute and delayed toxicities of lethal radiation exposure. The following Specific Aims will be tested: 1a) determine the optimal dosing regimen and delayed administration schedule of dmPGE2 in well-established young adult, pediatric, and Jackson Diversity Outbred mouse models of H-ARS, and b) perform PK of dmPGE2 in primates, 2) establish the transcriptional mechanisms affected when dmPGE2 is administered as a radiomitigator 24hr after exposure and identify the target hematopoietic cell population(s), and 3) explore combinatorial activity of dmPGE2 with: a) RP-1, a novel non-lipid LPA2 receptor agonist (with Dr. Tigyi), b) Neupogen®, and c) a novel senolytic MCM (with Dr. Zhou) to determine if co- administration provides superior efficacy in H-ARS and/or DEARE in mouse models compared to either MCM singly. Our data thus far combined with those from successful completion of this proposal will move dmPGE2 further towards development for approval as a MCM for use in a mass causality event for the benefit of mankind.