Development of lisinopril for post-exposure mitigation of late effects from a rad

开发赖诺普利以减轻辐射后的迟发效应

• 批准号: 8663191
• 负责人: MEETHA M MEDHORA
• 金额: $ 65.2万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8663191
• 关键词: Acute; Address; Adolescent; Angiotensin Receptor; Angiotensin-Converting Enzyme Inhibitors; Animal Model; Animals; Antibiotics; Attenuated; Award; Bone Marrow; Bone Marrow Cells; Bone Marrow Transplantation; CSF3 gene; Cancer Patient; Canis familiaris; Captopril; Cells; Childhood; Chronic; Clinic; Clinical Research; Clinical Trials; Development; Devices; Dose; Drug usage; Elderly; Enalapril; Energy Transfer; Event; Exposure to; Fibrosis; Functional disorder; Gamma Rays; Goals; Granulocyte Colony-Stimulating Factor; Hematopoietic; Hematopoietic stem cells; Hour; Human; Human Resources; IACUC; Immune; Injury; Ionizing radiation; Kidney; Kidney Diseases; Knock-out; Late Effects; Lead; Licensure; Linear Energy Transfer; Lisinopril; Lung; Measures; Mediating; Modeling; Molecular; Morbidity - disease rate; Multiple Organ Failure; Mutate; Neutrons; Nuclear; Organ; Organ failure; Outcome; Patients; Peptidyl-Dipeptidase A; Pharmaceutical Preparations; Physiological; Plasma; RNA; Radiation; Radiation Injuries; Radiation Pneumonitis; Radiation Syndromes; Radiation Toxicity; Rattus; Renin; Renin-Angiotensin System; Research; Retrospective Studies; Rodent Model; Roentgen Rays; Role; Simulate; Skin; Stem cell transplant; Supportive care; Survivors; Symptoms; Syndrome; Techniques; Terrorism; Testing; Therapeutic Agents; Thick; Training; Transplantation; Trauma; Whole-Body Irradiation; Work; Zinc Fingers; animal rule; base; improved; injured; irradiation; meetings; named group; next generation; novel; pre-clinical; prospective; public health relevance; radiation effect; transcriptome sequencing

DESCRIPTION (provided by applicant): Our research goal has been to mitigate radiation injuries to the lungs and kidneys. Mitigation is the use of a countermeasure after exposure to ionizing radiation but before symptoms develop. We have focused on a class of drugs, angiotensin converting enzyme (ACE) inhibitors, which have been used in the clinic for many indications. They have shown efficacy for mitigation of lethal radiation injuries to multiple organ in rats. We are now aiming to repurpose these drugs as mitigators for radiation-induced multiple organ failure, in survivors of acute hematological syndromes. Incidental use of these drugs by irradiated cancer patients decreased lung and kidney injuries. Since the ACE inhibitor lisinopril mitigates morbidity in rats when given 7 days after radiation, it fits the requirement of this U01 o be developed for post-exposure mitigation of injuries from a radiation or nuclear incident. We will address both purposes of this RFA. The first will be to further develop lisinopril by assessin efficacy post exposure in rats given total body irradiation. We will test lisinopril in combination with countermeasures proposed for the Strategic National Stockpile for use against acute radiation syndromes. We will also test lisinopril for mitigation after exposure to single low- and high-linear energy transfer irradiation (X-rays, neutron-gamma rays), and to radiation in combination with full thickness skin wounds that will occur from detonation of an improvised nuclear device. In addition we will evaluate efficacy in special populations (juvenile and geriatri rat models). For the second purpose of the U01, to elucidate the mechanism of action, we will use cutting-edge techniques to test a novel hypothesis to determine the molecular, cellular and physiological mechanism(s) of mitigation by lisinopril. These studies include next generation micro-ribonucleic acid sequencing (miRNA-Seq) and genetically altered (knock out) donor bone marrow transplantation in rats. Our results directly address the purposes of this RFA to advance lisinopril for licensure against radiation-induced multi-organ dysfunctions. We have organized an efficient as well as responsive research plan, team of experts and well trained personnel to meet our goals.

描述（由申请人提供）：我们的研究目标是减轻肺和肾的辐射损伤。缓解是指在暴露于电离辐射之后但在症状出现之前使用对策。我们关注的一类药物，血管紧张素转换酶（ACE）抑制剂，已在临床上用于许多适应症。它们已显示出减轻大鼠多器官致死性辐射损伤的功效。我们现在的目标是重新利用这些药物作为缓解辐射诱导的多器官衰竭，在急性血液综合征的幸存者。偶然使用这些药物的辐射癌症患者减少肺和肾损伤。由于ACE抑制剂赖诺普利在辐射后7天给药时可减轻大鼠的发病率，因此其符合本U 01的要求，即开发用于辐射或核事故损伤的暴露后缓解。我们将解决本RFA的两个目的。第一个将是通过评估全身照射大鼠暴露后的疗效来进一步开发赖诺普利。我们将测试赖诺普利与 并提出了用于预防急性辐射综合症的国家战略储备的对策。我们还将测试赖诺普利在暴露于单一的低和高线性能量转移照射（X射线，中子-γ射线）后的缓解作用，以及暴露于辐射结合简易核装置爆炸产生的全层皮肤伤口后的缓解作用。此外，我们将在特殊人群（幼龄和老年大鼠模型）中评价疗效。对于U 01的第二个目的，为了阐明作用机制，我们将使用尖端技术来测试一种新的假设，以确定赖诺普利缓解的分子、细胞和生理机制。这些研究包括下一代微核糖核酸测序（miRNA-Seq）和大鼠基因改变（敲除）供体骨髓移植。我们的研究结果直接解决了RFA的目的，以推进赖诺普利对辐射诱导的多器官功能障碍的许可。我们已经组织了一个有效的，以及响应研究计划，专家团队和训练有素的人员，以实现我们的目标。