Mitiagrion of Radiation Damage by Mechanisms of Innate Immune Regulation

日益增长的全球能源需求以及随之而来的核材料泄漏的威胁，无论是意外的还是故意的，都要求对如何治疗和减轻辐射伤害有更深入的了解。虽然许多研究描述了宿主对辐射损伤反应的性质，但已建立的模型为先天免疫在这一过程中的作用提供了非常令人信服的证据。肠道损伤后释放的病原体相关分子模式（Pathogen associated molecular patterns, PAMPs）刺激组织修复和宿主免疫途径。最近发现的一类由损伤细胞释放的内源性配体，损伤相关分子模式（damage associated molecular patterns, DAMPs），可以刺激一组类似的先天免疫受体，从而引发组织修复的相关程序。这些观察结果强调，辐射修复和宿主免疫涉及非常相似的基因程序。加州大学洛杉矶分校- cmcr已经确定了许多不同的化合物和小分子，可以成功地减轻辐射损伤；其中大多数激活了与病原体相似的途径。由此产生了一种新兴的理解，即成功的辐射缓解剂可以抑制过度炎症，并支持强大的再生基因程序，从而导致组织修复。这个

The increasing global energy demands and ensuing threat, be it accidental or intentional, of the release of nuclear material require a greater understanding of how to treat and mitigate radiation injury. While many studies describe the nature ofthe host response to radiation injury, established models provide very compelling evidence for a role for innate immunity in the process. Pathogen associated molecular patterns (PAMPs) released following gut injury stimulate tissue repair and host immune pathways. A recently described class of endogenous ligands released by injured cells, the damage associated molecular patterns (DAMPs), stimulate a similar group of innate immune receptors and so instigate a related program of tissue repair. These observations emphasize the point that very similar gene programs are involved in radiation repair and host immunity. The UCLA-CMCR has identified a number of different compounds and small molecules that are successful mitigators of radiation damage; the majority of which activate similar pathways as pathogens. From this comes the emerging understanding that a successful radiation mitigator suppresses excessive inflammation and supports robust regenerative gene programs leading to tissue repair. The optimal balance is exampled by lead compounds such as MIS416, an immune adjuvant that can successfully mediate crosstalk between Innate stimulation and radiation repair by regulating a number of signaling pathways. The same is true for other lead mitigators, such as IL-12, anti-inflammatory small molecules, or Tilorone, a type I interferon inducer. However, the molecular mechanisms responsible for mitigation remain unclear. In this application, we propose to discover which ofthe innate system pattern recognition receptors and which signal transduction pathways are required to support the mitigating activity of MIS416 and other UCLA-CMCR lead molecules. Furthermore, we will determine which genetic programs or cytokines contribute to the mitigating mechanism by inducing regeneration of hematopoietic stem cells. Thirdly, utilizing this increased understanding of the interaction between lead mitigators and innate immune regulatory systems, we shall develop a nanovesicle platform for radiation mitigation. Finally, we will examine a live vaccine model to explore the crosstalk between tissue repair mechanisms utilized in response to radiation injury and infection. Our proposed studies, by dissecting the receptors and pathways that mitigate radiation injury, will provide novel targets for therapeutic intervention and lead molecule verification. Our improved understanding ofthe similarities between responses activated by radiation and infection will drive design of additional novel strategies for intervention.