Triterpenoids in mitigation of radiation induced acute or delayed inflammation

三萜类化合物可减轻辐射引起的急性或迟发性炎症

基本信息

批准号：
10852214
负责人：
Richard J DiPaolo
金额：
$ 13.42万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-21 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10852214
关键词：
Acids Acute Address Aftercare Agonist Anti-Inflammatory Agents Antineoplastic Agents Antioxidants Bone Marrow CCL2 gene CCR Cell Culture Techniques Cell Proliferation Cells Chemical Injury Chemicals Chest Circulation Clinical Trials Collaborations Data Development Dose Esters Exposure to Eye Injuries Fibrosis Funding Gastrointestinal tract structure Gene Deletion Genes Grant Hour Immune Inflammation Inflammation Mediators Inflammatory Injury Laboratories Licensure Ligands Lung Modeling Mucous Membrane Multiple Organ Failure Mus Myelogenous Myeloid Cells NQO1 gene National Institute of Allergy and Infectious Disease Nuclear Nuclear Accidents Oleanolic Acid Organ Oxidative Stress Oxidative Stress Induction Parents Pathway interactions Play Population Production Publishing Pulmonary Fibrosis Pulmonary Inflammation Radiation Radiation Accidents Radiation Injuries Radiation Syndromes Radiation Toxicity Radiation exposure Radiation induced damage Radio Rationalization Reporting Research Resistance Risk Role Schedule Signal Transduction Site Syndrome T-Lymphocyte Terpenes Terrorism Testing Tissues Toxic effect Validation Work animal rule chemical countermeasure chemokine chemokine receptor efficacy study epithelial injury gastrointestinal heme oxygenase-1 injured irradiation jejunum mass casualty medical countermeasure monocyte mouse model nuclear factor-erythroid 2 oleanane pre-clinical programs radiation mitigation radiation resistance radioresistant recruit systemic inflammatory response tissue injury

项目摘要

Project Summary Currently, there is a need for strategies that mitigate acute and delayed radiation syndrome. The risk of large populations encountering radiation exposure is real and growing. Radiation induced inflammation plays significant role in inducing radiation toxicity. Chemokine signaling plays key role in systemic and local inflammation by modulating egress and recruitment inflammatory immune cells such as inflammatory monocytes and T cells. Radiation exposure induces recruitment of inflammatory cells and promotes systemic and local inflammation. We have observed that deletion of genes expressing chemokine receptor 2 in mice promotes resistance radiation induced acute and delayed inflammation. Triterprenoids are very potent anti-inflammatory agents. Recent findings suggest that synthetic derivatives of oleanolic acid that are more potent at suppressing production of the inflammatory mediator such as chemokine ligand 2. Under NIAID Chemical Countermeasures Research Program (CCRP) Triterprenoids such as CDDO- methyl ester (CDDO-Me) has been shown to mitigate chemical induced ocular injury by nrf2 dependent manner. In this proposal we will examine the effect of CDDO- Me against radiation induced acute and delayed inflammation using mice model of radiation induced gastrointestinal syndrome and radiation induced pulmonary syndrome respectively. We will also characterize the effect of CDDO-Me in modulation of bone marrow derived inflammatory immune cell recruitment in injured tissue. Determination of mechanism of action of will facilitate CDDO-Me as a medical countermeasure against radiation under the FDA’s Animal Rule.

项目概要目前，需要减轻急性和迟发性辐射综合症风险的策略。遭受辐射照射的人群是真实存在的，并且辐射引起的炎症正在增加。在诱导辐射毒性中发挥重要作用趋化因子信号在全身和局部中发挥关键作用。通过调节炎症免疫细胞（例如炎症单核细胞）的排出和募集来消除炎症辐射暴露会诱导炎症细胞的募集并促进全身和局部的炎症细胞的聚集。我们观察到，删除小鼠中表达趋化因子受体 2 的基因会促进炎症。抵抗辐射引起的急性和迟发性炎症。三萜类化合物具有非常有效的抗炎作用。最近的研究结果表明，齐墩果酸的合成衍生物具有更有效的抑制作用。趋化因子配体等炎症介质的产生 2. 根据 NIAID 化学对策研究计划 (CCRP) 三萜类化合物如 CDDO-甲酯 (CDDO-Me) 已被证明可以缓解化学物质通过 nrf2 依赖性方式引起的眼损伤在本提案中，我们将检查 CDDO- 的作用。使用辐射小鼠模型对抗辐射引起的急性和迟发性炎症我们还将分别诱发胃肠道综合征和辐射诱发肺部综合征。表征 CDDO-Me 在调节骨髓源性炎症免疫细胞中的作用确定其作用机制将有助于 CDDO-Me 作为医疗药物。 FDA 动物规则下的辐射对策。