Radioprotection of the immune system

免疫系统的辐射防护

• 批准号: 7665498
• 负责人: WILLIAM H. MCBRIDE
• 金额: $ 35.05万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7665498
• 关键词: Activated Lymphocyte; Activities of Daily Living; Androstenes; Antigen Presentation Pathway; Apoptosis; Biological; Biological Assay; Cannabinoids; Cell Survival; Cell physiology; Cell-Mediated Cytolysis; DNA Repair; Defect; Dendritic Cells; Development; Developmental Therapeutics Program; Effectiveness; Fatty Acids; Focus Groups; Human; Immune; Immune system; Immunity; In Vitro; International; Libraries; Ligands; Lipids; Luciferases; Lymphocyte; Modeling; Molecular Profiling; Mus; NF-kappa B; Normal tissue morphology; Orphan; Phosphoric Monoester Hydrolases; Primates; Property; Proteome; Proteomics; Quinolones; Radiation; Radiation Interaction; Radiation induced damage; Radiation therapy; Radiation-Induced Change; Radioprotection; Reporter Genes; Screening Result; Screening procedure; Signal Pathway; Signal Transduction Pathway; Staging; T-Lymphocyte; Testing; Tissues; Toll-like receptors; Toxicity Tests; Whole-Body Irradiation; Yeasts; antigen processing; apoptosis in lymphocytes; base; carcinogenesis; cytotoxicity; high throughput screening; improved; in vivo; in vivo Bioassay; ion channel blocker; irradiation; kinase inhibitor; prevent; protein expression; radiation effect; receptor; small molecule; small molecule libraries

Immune suppression is one of the most common and most serious consequences of whole body radiatior exposure. If radiation-induced immune suppression is to be prevented or alleviated an improved mechanistic understanding of the subtleties of the interaction of radiation with the immune system is needed. This proposal focuses on two important aspects of radiation-induced immune suppression in a murine model. The first is radiation-induced apoptosis of lymphocytes. The second is the deleterious effects of radiation on dendritic cell (DC) function. We recently described this effect of radiation and believe it may be an important mechanism of immune suppression. In contrast to lymphocytes, which die readily by apoptosis, DCs resist radiation cytotoxicity but their functional ability to process antigen and generate immunity is abrogated. The essential thread of the proposal is that defining agents by the signal transduction pathways the activate and their effects on the proteome is essential for rational development of products capable of protection, mitigation, and therapy of radiation-induced immune suppression. In this project lymphocytes and DCs will be targets for high (HTS) screening of chemical libraries, alongside compounds with known or suspected potential, with the aim of identifying compounds that inhibit radiation lymphocyte cytotoxicity and activate protective signaling pathways in DCs, initially for NF-kappaB but later other reporter gene assays. The results of these screens will be compared with those from yeast radiation-induced DMA damage (Project 1) and, based on potency and biological effects, a subset of agents will be chosen for proteomic screening to broaden their molecular profiling, for testing in in vivo bioassays for immune protection and enhancement, and for their ability to modulate radiation damage in multiple normal tissues. Although this project has an immune focus, the effects of agents on radiation-induced damage in multiple tissues will be determined to see if they have broad effectiveness, or do harm. This study will also help elucidate the interrelationships between agents and critical signal transduction pathways influencing DNA repair, cell survival, and carcinogenesis.

免疫抑制是全身辐射暴露最常见和最严重的后果之一。如果要预防或减轻辐射引起的免疫抑制，就需要对辐射与免疫系统相互作用的微妙机制有更好的理解。该提案重点关注小鼠模型中辐射诱导的免疫抑制的两个重要方面。第一个是辐射诱导的淋巴细胞凋亡。第二个是辐射对树突状细胞（DC）功能的有害影响。我们最近描述了辐射的这种效应，并认为它可能是免疫抑制的重要机制。与容易因细胞凋亡而死亡的淋巴细胞相比，DC 具有抵抗力 放射细胞毒性，但它们处理抗原和产生免疫力的功能被消除。该提案的基本思路是，通过激活信号转导途径及其对蛋白质组的影响来定义药物，对于合理开发能够保护、缓解和治疗辐射诱导的免疫抑制的产品至关重要。在该项目中，淋巴细胞和树突状细胞将成为化学库高（HTS）筛选的目标，以及具有已知或可疑潜力的化合物，目的是识别抑制辐射淋巴细胞细胞毒性并激活树突状细胞中保护性信号传导途径的化合物，最初用于NF- kappaB 以及后来的其他报告基因检测。这些筛选的结果将与酵母辐射诱导的 DMA 损伤（项目 1）的结果进行比较，并且根据效力和生物效应，将选择一部分药物进行蛋白质组筛选，以扩大其分子谱，以便在中进行测试。用于免疫保护和增强的体内生物测定，以及调节多种正常组织辐射损伤的能力。尽管该项目以免疫为重点，但仍将确定药物对多个组织中辐射引起的损伤的影响，以确定它们是否具有广泛的有效性或是否会造成伤害。这项研究还将有助于阐明影响 DNA 修复、细胞存活和影响的关键信号转导途径之间的相互关系。 致癌作用。