Mitigation of Radiation Injury via Vascular Regeneration and Remodeling

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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.