Mitigation of Radiation Damage to the Immunohematopoietic System

减轻辐射对免疫造血系统的损伤

• 批准号: 8542323
• 负责人: WILLIAM H. MCBRIDE
• 金额: $ 4.01万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-31 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8542323
• 关键词: Adverse effects; Ally; Animals; Binding; Biological; Biological Assay; Characteristics; Chemicals; Collaborations; Colony-Forming Units Assay; DNA Repair; Data; Databases; Development; Disasters; Effectiveness; Epithelial Cells; Funding; Future; Goals; Hematopoiesis; Homeostasis; Interferon Inducers; Knowledge; Libraries; Ligands; Link; Metals; Mining; Molecular; Pathway interactions; Patients; Pilot Projects; Polyunsaturated Fatty Acids; Purine Nucleosides; Purinergic P1 Receptors; Quinolones; Radiation; Recovery; Stem cells; System; Tetracyclines; Time; Tissues; Toll-Like Receptor Pathway; Toll-like receptors; Work; Yeasts; analog; antimicrobial; cyclopiazonic acid; design; high throughput screening; improved; in vitro Assay; in vivo; novel; nucleoside analog; pharmacophore; response; small molecule; small molecule libraries; theories; tissue regeneration

The primary aim of Project 2 was to use unbiased high throughput screening (HTS) of small molecule libraries allied to more targeted approaches to identify novel compounds that would protect and mitigate against radiation damage, primarily to the immunohematopoietic system but also other tissues. The theory was that active compounds would possess a molecular and/or chemical signature that could be identified and optimized to benefit the development of superior agents for Stockpiling in case of a radiologic disaster. We have shown that tetracyclines, quinolones, and cyclopiazonic acid can act as radiation mitigators, independent of any anti-microbial action. Furthermore, they share a common metal-binding pharmacophore. The importance of this substructure for mitigation will be studied in the next funding period. Other active mitigators included purine nucleosides. We intend to explore this avenue further using new compounds that are specific for differentially expressed subtypes of adenosine receptors so as to minimize possible mutually antagonistic actions and side effects resulting from the use of these agents. Linoleate and other polyunsaturated fatty acids also showed mitigating activity, as did several other agents that are directed to Toll-like receptors or are products of these pathways. This link will be investigated furter in collaboration with Project 3. Compounds from the chemically defined libraries that were positive in our screens will be investigated further along with Project 1, which showed that two ofthe compounds were positive in yeast DEL HTS assays and in vivo as mitigators. Our working hypothesis is that radiation initiates continuing "waves" of integrated molecular and cellular responses that are aimed at tissue regeneration and that multiple mitigators may be needed, perhaps given at different times, to rebalance tissue homeostasis. This will require mechanistic knowledge of how these mitigators work. We have shown effects ranging from DNA repair to stimulating hematopoiesis to long-term animal survival. In vitro assays will be extended to include novel epithelial and stem cell assays developed through the Pilot Project mechanism and in vivo assays will be extended to include better coverage of effects of sublethal damage and stem cell recovery.

项目 2 的主要目标是使用小分子的无偏高通量筛选 (HTS) 图书馆联合更有针对性的方法来识别能够保护和减轻影响的新型化合物 对抗辐射损伤，主要是针对免疫造血系统，还有其他组织。理论 活性化合物将拥有可以识别的分子和/或化学特征 并进行了优化，以有利于开发在发生放射灾难时进行储存的优质药剂。 我们已经证明四环素类、喹诺酮类和环吡嗪酸可以作为辐射缓解剂， 独立于任何抗微生物作用。此外，它们具有共同的金属结合药效基团。 该子结构对于缓解的重要性将在下一个资助期间进行研究。其他活跃 缓解剂包括嘌呤核苷。我们打算使用新化合物进一步探索这一途径 对腺苷受体的差异表达亚型具有特异性，以最大限度地减少可能的相互影响 使用这些药物产生的拮抗作用和副作用。亚油酸酯及其他 多不饱和脂肪酸也显示出缓解活性，其他几种针对 Toll 样受体是这些途径的产物。将与以下机构合作进一步调查此链接 项目 3. 来自化学定义库的在我们的筛选中呈阳性的化合物将被 与项目 1 一起进一步研究，结果表明其中两种化合物在酵母中呈阳性 DEL HTS 测定和体内作为缓解剂。我们的工作假设是辐射会引发持续的 旨在组织再生的综合分子和细胞反应的“波” 可能需要多种缓解剂，也许在不同时间给予，以重新平衡组织稳态。这 将需要了解这些缓解剂如何工作的机械知识。我们已经展示了从 DNA 到 修复刺激造血以实现动物的长期生存。体外测定将扩展到包括 通过试点项目机制和体内测定开发的新型上皮细胞和干细胞测定将 扩展到包括更好地覆盖亚致死损伤和干细胞恢复的影响。