Mitigation of Radiation Injury via Vascular Regeneration and Remodeling

通过血管再生和重塑减轻放射损伤

• 批准号: 10623173
• 负责人: John P Chute
• 金额: $ 60.1万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-05 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10623173
• 关键词: Academia; Acute; Affect; Animal Model; Cells; Chronic; Development; Disease; Dose; Drug Delivery Systems; Drug Kinetics; Drug Modelings; Education; Ensure; Exposure to; FDA approved; Formulation; Germ-Free; Gnotobiotic; Goals; Hematology; Hematopoietic; Homeostasis; Immune system; Industry; Inflammation; Infrastructure; Intellectual Property; Intestines; Longevity; Modeling; Morbidity - disease rate; Mouse Strains; National Institute of Allergy and Infectious Disease; Natural regeneration; New Agents; Organ; Oxidative Stress; Pathway interactions; Pharmaceutical Preparations; Pilot Projects; Polypharmacy; Pulmonary Fibrosis; Radiation; Radiation Dose Unit; Radiation Injuries; Radiation Pneumonitis; Radiation Syndromes; Radiation Toxicity; Radiation exposure; Radiation induced damage; Research Personnel; Role; Services; Signal Pathway; Solubility; Structure; Syndrome; Testing; Tissues; Vascular regeneration; Vascular remodeling; chemical synthesis; cohesion; drug development; healing; improved; interest; member; mortality; novel; programs; radiation mitigation; radiation mitigator; response; targeted agent

The theme of the UCLA-CMCR Program is to discover and develop novel and unique drugs, or to repurpose existing agents, that mitigate acute, delayed, and long-term radiation syndromes. We have already identified over 30 mitigators of hematopoietic acute radiation syndrome (H- ARS), some of which are in quite advanced drug development. Some are effective in multiple models of acute, delayed and long-term radiation tissue damage, which makes them of particular interest as every cell in the body is damaged after exposure to moderate doses of radiation and polypharmacy to mitigate every syndrome would be almost impossible to achieve. We believe that broad activity results from action through primitive, highly conserved, developmental signaling pathways that are responsible for the formation of body structures, but that also guide regeneration in damaged tissues and regulate chronic inflammation. The role of these pathways in diverse radiation syndromes, acute and delayed, form a major theme in this application. Our Projects will therefore extend our portfolio of mitigators with an emphasis on developmental signaling pathways in multiple tissues. Two focus on Acute syndromes and two on late syndromes. We believe that delayed effects of acute radiation exposure (DEARE) are due to incomplete healing during H-ARS, resulting in skewing of the immune system that generates persistent oxidative stress, chronic inflammation, and dysregulated homeostasis in multiple tissues. This is consistent with our finding that mitigation of H-ARS by drugs that trigger developmental pathway signaling can affect DEARE. Our Service Cores are geared to drug and animal model optimization. They will improve the efficacy and delivery of drugs through FDA-approved formulation and chemical synthesis that aims to improve solubility, pharmacokinetics, mechanisms of action, and uniqueness of matter. The animal models will have pathophysiologically-defined, dose-response relationships for acute and delayed endpoints of morbidity and mortality using gnotobiotic and germ-free mouse strains. Comparisons will be made to the effects of FDA-approved H-ARS mitigators in these diverse radiation syndromes. The Administrative Core serves to integrate projects, service cores, and pilot projects and provides a conduit to the CMCRC, governmental bodies, industry, and academia. It provides cohesion for the UCLA-CMCR and ensures that it meets the common goals established by NIAID, the FDA, and the CMCRC. It also provides an educational infrastructure for members and its Executive Committee helps investigators prioritize drugs for development and testing, and with regulatory and intellectual property issues.

UCLA-CMCR计划的主题是发现和 开发新型和独特的药物，或重新利用现有的药物，以减轻急性，延迟， 长期辐射综合征我们已经确定了30多种造血急性 辐射综合征（H-ARS），其中一些药物开发相当先进。有些是 在急性、延迟和长期放射性组织损伤的多种模型中有效， 它们特别令人感兴趣，因为身体中的每个细胞在暴露于中等剂量的 用放射和多种药物来减轻每一种综合症几乎是不可能实现的。我们 我认为，广泛的活动是通过原始的、高度保守的、发展的 信号通路负责身体结构的形成，但也指导 促进受损组织再生并调节慢性炎症。这些途径在 各种各样的辐射综合征，急性的和延迟的，形成了本申请的主要主题。我们的项目 因此，我们将扩大我们的缓解剂组合，重点是发育信号通路 在多个组织中。两个集中在急性综合征和两个晚综合征。我们认为 急性辐射暴露的延迟效应（DEARE）是由于H-ARS期间的不完全愈合， 导致免疫系统的偏斜，产生持续的氧化应激、慢性 炎症和多种组织中的失调的稳态。这与我们的发现一致， 通过触发发育途径信号传导的药物缓解H-ARS可影响DEARE。我们 服务核心是面向药物和动物模型优化。它们将提高疗效， 通过FDA批准的配方和化学合成提供药物，旨在改善 溶解性、药代动力学、作用机制和物质的独特性。动物模型将 急性和延迟终点具有病理生理学定义的剂量-反应关系， 使用无菌和无菌小鼠品系的发病率和死亡率。将与以下各项进行比较： FDA批准的H-ARS缓解剂在这些不同辐射综合征中的作用。的 行政核心服务于整合项目、服务核心和试点项目， CMCRC、政府机构、行业和学术界的渠道。它为 UCLA-CMCR，并确保其符合NIAID，FDA和 CMCRC。它还为会员提供教育基础设施，其执行委员会帮助 研究人员优先考虑开发和测试以及具有监管和知识产权的药物 问题.