Radioprotection of the immune system

免疫系统的辐射防护

• 批准号: 7465606
• 负责人: WILLIAM H. MCBRIDE
• 金额: $ 36.6万
• 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/7465606
• 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的最常见和最严重的后果之一。如果要预防辐射诱导的免疫抑制或减轻对辐射与免疫系统相互作用的微妙的改进的机械理解。该提议着重于鼠模型中辐射诱导的免疫抑制的两个重要方面。首先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影响，并认为它可能是免疫抑制的重要机制。与凋亡容易死亡的淋巴细胞相反，DCS抵抗 辐射细胞毒性，但它们的处理抗原和产生免疫力的功能能力被废除了。该提案的基本线索是，通过信号转导途径定义药物，激活及其对蛋白质组的影响对于合理开发能够保护，缓解和治疗放射辐射诱导的免疫抑制的产品至关重要。在这个项目中，淋巴细胞和DC将是对化学库的高（HTS）筛查的靶标，以及具有已知或可疑潜力的化合物，目的是鉴定抑制辐射淋巴细胞毒性的化合物，可抑制辐射型细胞毒性并激活DC中的DC中的DC，最初是NF-Kapababab的cans nf-kappab and recorter gene gene。这些筛选的结果将与酵母辐射引起的DMA损伤的结果进行比较（项目1），并且，根据效力和生物学效果，将选择一部分用于蛋白质组学筛选以扩大其分子筛选，以扩大在体内生物测定的测试，以对其进行免疫保护和增强的能力调节多个正常组织，以调节多个正常组织。尽管该项目具有免疫焦点，但将确定药物对辐射诱导的多个组织损伤的影响，以查看它们是否具有广泛的效率或损害。这项研究还将有助于阐明药物之间的相互关系以及影响DNA修复，细胞存活和的关键信号转导途径 致癌作用。