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

开发 dmPGE2 和 Bcl-xl 靶向 senolytics 作为 H-ARS 和 DEARE 的医疗对策

• 批准号: 10401459
• 负责人: CHRISTIE M Orschell
• 金额: $ 23.01万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-16 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10401459
• 关键词: Accidents; Acute; Advanced Development; Affect; Age; Aging; Agonist; Animal Model; Animals; BCL2L1 gene; Benign; Biology; Blood; Bone Marrow; CSF3 gene; Cardiac; Cells; Cessation of life; Childhood; Chronic Disease; Collaborations; Data; Depressed mood; Development; Dinoprostone; Dose; Edg4 Protein; Eicosanoids; Elderly; Environment; Etiology; Event; Exposure to; FDA approved; Filgrastim; General Population; Genetic Transcription; Goals; Grant; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematologist; Hematopoiesis; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; Hemorrhage; Human; Human Resources; Inbreeding; Individual; Infection; Joints; Kidney; Life; Lymphoid; Medical Research; Modeling; Molecular; Mus; National Institute of Allergy and Infectious Disease; Natural regeneration; Nuclear Accidents; Pegfilgrastim; Polypharmacy; Population; Populations at Risk; Primates; Radiation; Radiation Accidents; Radiation Dose Unit; Radiation Injuries; Radiation Protection; Radiation Syndromes; Radiation Toxicity; Radiation exposure; Radiation induced damage; Radiology Specialty; Recovery; Regimen; Research Personnel; Residual state; Schedule; Survivors; System; Testing; Time; Tissues; Toxic effect; animal rule; base; body system; combinatorial; efficacy study; hematopoietic stem cell fate; irradiation; lung injury; medical countermeasure; mouse model; nonhuman primate; novel; programs; radiation countermeasure; radiation mitigator; repaired; response; sargramostim; senescence; stem cell biology; survival outcome; treatment effect; warfighter; young adult

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.

涉及辐射的恐怖事件的威胁日益增加，以及发生辐射事故的可能性， 强调了对辐射采取有效医疗对策的必要性。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）， 高剂量辐射暴露和感染死亡和/或如果不治疗出血。H-ARS的幸存者 由于急性辐射暴露的延迟效应（DEARE），一些慢性疾病影响了 多器官系统迄今为止，Neupogen（粒细胞集落刺激因子，G-CSF）、Neulasta （聚乙二醇化-G-CSF）和Leukine®（GM-CSF）是FDA批准用于治疗H-ARS的唯一MCM， 并将作为暴露于高剂量辐射的个人的一线治疗。这项提议带来了 与唯一合格的研究人员一起进行长期的富有成效的合作，研究16，16 二甲基前列腺素E2（dmPGE 2）在H-ARS和DEARE和造血再生。Orschell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并验证了H-ARS模型 和菌株。Pelus博士是造血干细胞生物学和类花生酸生物学的领导者。在一起，Co- PI已经表明，在致死辐射暴露后30小时给予单剂量dmPGE 2， 提高30天存活率和造血恢复。与合作者米勒博士，该小组已经表明， 在照射前给予dmPGE 2作为辐射防护剂， 心脏和肾脏疾病。然而，dmPGE 2，也不是上面列出的三种许可的MCM中的任何一种，已经显示出 当作为放射性抑制剂（照射后）给药时，DEARE的疗效。合作者周博士，DEARE专家 和衰老，最近加入了该小组，以测试新的Bcl-xl靶向衰老剂的能力， 减轻用dmPGE 2作为放射性激动剂处理的小鼠中的DEARE。PI将检验dmPGE 2 满足H-ARS理想MCM的所有要求，并且当与幸存者中的senolytics结合使用时， 这体现了一种有效的战略，以减轻致命辐射照射的急性毒性和延迟毒性。的 将测试以下特定目的：1a）确定最佳给药方案和延迟给药 在成熟的年轻成人、儿童和杰克逊多样性远系小鼠模型中的dmPGE 2时间表 和B）在灵长类动物中进行dmPGE 2的PK，2）建立受影响的转录机制， 在暴露后24小时给予dmPGE 2作为放射性激动剂，并鉴定靶造血细胞 群体，和3）探索dmPGE 2与以下的组合活性：a）RP-1，一种新的非脂质LPA 2受体 激动剂（与Tigyi博士），B）Neupogen®，和c）一种新的衰老清除剂MCM（与Zhou博士），以确定是否存在共 在小鼠模型中，与MCM或MCM给药相比，在H-ARS和/或DEARE方面提供了上级功效。 一个人迄今为止，我们的数据与成功完成该提案的数据相结合，将使dmPGE 2 进一步发展，以批准作为MCM用于大规模因果关系事件，造福人类。