Mitiagrion of Radiation Damage by Mechanisms of Innate Immune Regulation

通过先天免疫调节机制减轻辐射损伤

• 批准号: 8011751
• 负责人: GENHONG CHENG
• 金额: $ 36.38万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-05 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8011751
• 关键词: Accidents; Adjuvant; Affect; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Attenuated; Attenuated Live Virus Vaccine; Attenuated Vaccines; Bone Marrow; Cells; DNA Repair; Development; Disasters; Dose; Equilibrium; Event; Exposure to; Family; Genes; Genetic Programming; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Immune; Immune response; Immunity; Immunologic Adjuvants; Immunologic Receptors; Immunologics; Individual; Infection; Inflammation; Inflammatory; Injury; Instruction; Interferon Inducers; Interferon Type I; Interleukin-12; Ionizing radiation; Lead; Libraries; Life; Ligands; Mediating; Modeling; Molecular; Mus; Natural Immunity; Natural regeneration; Nature; Nuclear; Overlapping Genes; Pathway interactions; Pattern; Pattern recognition receptor; Pharmaceutical Preparations; Population; Process; Radiation; Radiation Injuries; Radiation Tolerance; Reaction; Reagent; Recovery; Regulation; Role; Signal Pathway; Signal Transduction Pathway; Source; Stem cells; System; Therapeutic; Therapeutic Intervention; Tilorone; Toll-like receptors; Vaccines; Whole-Body Irradiation; Wound Healing; base; cell injury; cytokine; design; fighting; gastrointestinal system; high throughput screening; improved; injured; injury and repair; interest; mouse model; nanoparticle; next generation; novel; novel strategies; oral vaccine; pathogen; programs; radiation recovery; receptor; regenerative; repaired; response; small molecule; tool; tool development; weapons

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.

全球能源需求的增加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，都要求人们更好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反应的性质，但已建立的模型为先天免疫在此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（PAMP）刺激组织修复和宿主免疫途径。最近描述的一类由损伤细胞释放的内源性配体，损伤相关分子模式（DAMP），刺激类似的先天免疫受体组，从而引发组织修复的相关程序。这些观察结果强调了一点，即非常相似的基因程序参与辐射修复和宿主免疫。UCLA-CMCR已经确定了许多不同的化合物和小分子，它们是辐射损伤的成功缓解剂;其中大多数激活与病原体相似的途径。由此产生了一种新的认识，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。的 最佳平衡的例子是先导化合物，如MIS 416，一种免疫佐剂，可以成功地 通过调节许多信号传导来介导先天刺激和辐射修复之间的串扰 途径。其他铅缓解剂也是如此，如IL-12、抗炎小分子或 替洛龙，一种I型干扰素诱导剂。然而，负责缓解的分子机制仍然存在， 不清楚在这个应用中，我们提出要发现哪些先天系统的模式识别受体 以及需要哪些信号转导途径来支持MIS 416和其他 UCLA-CMCR先导分子。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而有助于缓解机制。第三，利用 这增加了对铅缓解剂和先天免疫调节剂之间相互作用的理解， 系统，我们将开发一个用于减轻辐射的纳米囊泡平台。最后，我们将研究一个活的 疫苗模型，以探索组织修复机制之间的串扰，用于响应辐射 损伤和感染。我们提出的研究，通过解剖受体和途径，减轻辐射 损伤，将提供新的治疗干预和先导分子验证的目标。我们改进的 了解辐射和感染激活的反应之间的相似性将推动设计 新的干预策略。