Mitiagrion of Radiation Damage by Mechanisms of Innate Immune Regulation

全球日益增长的能源需求以及随之而来的核材料泄漏威胁--无论是意外的还是故意的--要求更多地了解如何治疗和减轻辐射伤害。虽然许多研究描述了宿主对辐射损伤的反应的性质，但已建立的模型提供了非常令人信服的证据，证明先天免疫在这一过程中发挥了作用。肠道损伤后释放的病原体相关分子模式(PAMPs)可刺激组织修复和宿主免疫途径。损伤细胞释放的一类内源性配体，即损伤相关分子模式(DAMP)，可以刺激类似的一组天然免疫受体，从而启动相关的组织修复程序。这些观察结果强调了一个观点，即非常相似的基因程序参与了辐射修复和宿主免疫。加州大学洛杉矶分校的CMCR已经确定了一些不同的化合物和小分子，它们成功地减轻了辐射损害；其中大多数激活了与病原体相似的途径。由此产生了一种新的理解，即成功的辐射缓释剂可以抑制过度的炎症，并支持导致组织修复的强大的再生基因计划。这个 最优平衡的例子是先导化合物，如MIS416，一种免疫佐剂，可以成功地 通过调节一些信号来调节先天刺激和辐射修复之间的串扰 小路。对于其他铅缓释剂也是如此，如IL-12、抗炎小分子或 Tilorone，一种I型干扰素诱导剂。然而，导致缓解的分子机制仍然存在。 不清楚。在这一应用中，我们建议发现哪些天生的系统模式识别受体 以及需要哪些信号转导通路来支持MIS416和其他 UCLA-CMCR铅分子。此外，我们将确定哪些遗传程序或细胞因子 通过诱导造血干细胞的再生，有助于缓解机制。第三，利用 这增加了对铅缓释剂和先天免疫调节之间相互作用的理解。 在这些系统中，我们将开发一个用于辐射缓解的纳米微囊平台。最后，我们将审查一位现场直播 探索辐射反应中组织修复机制之间的串扰的疫苗模型 受伤和感染。我们建议的研究，通过解剖受体和减轻辐射的途径 损伤，将为治疗干预和铅分子验证提供新的靶点。我们改进了 了解辐射和感染激活的反应之间的相似性将推动 其他新的干预策略。

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.