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: 10194367
• 负责人: CHRISTIE M Orschell
• 金额: $ 23.83万
• 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/10194367
• 关键词: Accidents; Acute; Advanced Development; Affect; Age; Aging; Agonist; Animal Model; Animals; 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.

恐怖事件的日益严重的威胁涉及辐射以及辐射事故的潜力， 强调需要有效的医疗对策（MCM）抵抗辐射。血液形成系统 是辐射最敏感的组织，导致造血急性辐射综合征（H-ARS） 如果未治疗，高剂量的辐射暴露和死亡和/或出血。 H-ARS患者的幸存者 生命的后期因急性辐射暴露的延迟影响（亲爱的），许多慢性疾病影响 多器官系统。迄今为止，Neupogen（粒细胞 - 固体刺激因子，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 并将作为暴露于高剂量辐射的个体的一线治疗。该提议带来了 共同合格的研究人员与长期的生产协作一起研究了16,16的效率 Hars和Deare和造血再生中的二甲基前列腺素E2（DMPGE2）。 Orschell博士是 放射生物学家和实验血液学家，他们在各个年龄段的小鼠中开发和验证了H-AR的模型 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。一起，共同 PIS表明，致命辐射暴露后，单剂量的DMPGE2高达30小时，显着 增强了30天的生存和造血恢复。与合作者米勒博士一起，该团队表明 辐射之前，DMPGE2作为放射保护剂给出，可显着缓解造血，淋巴样， 心脏和肾脏亲爱的。但是，DMPGE2，也没有上述三个许可的MCM中的任何一个 当作为放射线剂时（辐照后）给予亲爱的效率。 Deare的专家Zhou博士合作者 和Sentcenting，最近加入了该小组，测试了新型BCl-XL靶向鼻溶剂的能力 在用DMPGE2治疗的小鼠中，减轻了Deare。 PI将检验DMPGE2的假设 满足H-AR的理想MCM的所有要求，并在与Senolotics结合使用时， 体现了减轻致命辐射暴露的急性和延迟毒性的有效策略。 将测试以下特定目标：1A）确定最佳给药方案和延迟给药 成年人，小儿和杰克逊多样性鼠标模型的DMPGE2的时间表 h-ars和b）在私人中执行dmpge2的pk，2）建立影响时的转录机制 暴露后24小时以24小时为单位施用DMPGE2，并识别靶造血细胞 种群和3）探索DMPGE2的组合活性与：a）RP-1，一种新型的非脂质LPA2受体 激动剂（与Tigyi博士），b）Neupogen®和C）新型的鼻溶性MCM（与Zhou博士一起），以确定是否共同 与任何一种MCM相比 单独迄今为止，我们的数据与该提案成功完成的数据相结合，将移动DMPGE2 进一步发展成为大规模因果事件的MCM批准，以使人类受益。