Modulation of chemokine signaling to mitigate radiation induced inflammation

调节趋化因子信号传导以减轻辐射引起的炎症

基本信息

批准号：
10669126
负责人：
Richard J DiPaolo
金额：
$ 68.09万
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/10669126
关键词：
Acute Affect Aftercare Animals Anti-Inflammatory Agents Antineoplastic Agents Atherosclerosis B-Lymphocytes Basophils Bone Marrow Bone Marrow Involvement Cell Lineage Cells Circulation Data Development Disease Dose Early treatment Exposure to Extramedullary FOXP3 gene Face Gene Deletion Hematopoietic Hour Human Immune Immune response Inflammation Inflammatory Inflammatory Response Injury Intestines Knockout Mice Licensure Lung Lymphocyte Modeling Multiple Organ Failure Mus Myelogenous Myeloid Cells Nuclear Nuclear Accidents Organ Peritoneal Macrophages Play Population Pulmonary Fibrosis Radiation Radiation Accidents Radiation Injuries Radiation Syndromes Radiation Toxicity Radiation exposure Regulatory T-Lymphocyte Research Resistance Rheumatoid Arthritis Risk Role Schedule Signal Transduction Site Structure of parenchyma of lung Surface Syndrome T memory cell T-Lymphocyte Terrorism Testing Therapeutic Time Tissues Toxic effect Whole-Body Irradiation aged animal rule antagonist chemokine chemokine receptor effector T cell experimental study gastrointestinal in vivo inhibitor inhibitor therapy injured intestinal injury irradiation mass casualty medical countermeasure monocyte mouse model multiorgan damage pharmacologic programs radiation effect radiation mitigation radiation resistance radioresistant recruit repair function therapeutic evaluation therapeutic target tissue repair trafficking

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 radiation resistance. Pharmacological inhibition of CCR2 signaling mitigates acute radiation syndrome in mice. Moreover these animals receiving CCR2 antagonist treatment did not develop delayed effect of acute radiation exposure (DEARE) such as radiation induced pulmonary syndrome. In this proposal we will examine the effect of CCR2 inhibitor against radiation induced acute and delayed inflammation using mice model of acute and delayed radiation injury. We will fully characterize CCR2 antagonist treatment with a determination of an optimum dose and schedule for mitigation of radiation induced acute and delayed inflammation. We will examine the general applicability of this strategy in young and aged animals. We will also characterize the effect of CCR2 antagonist in in modulation of bone marrow derived inflammatory immune cell release and recruitment in injured tissue. Determination of mechanism of action of will facilitate CCR2 inhibitor 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（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。 CCR2 信号传导综合征的药理学抑制可减轻小鼠的急性辐射综合征。此外，这些动物的 CCR2 拮抗剂治疗并未产生急性辐射的延迟效应暴露（DEARE），例如辐射引起的肺综合征，在本提案中我们将检查其影响。使用急性和迟发性炎症小鼠模型研究 CCR2 抑制剂对辐射引起的急性和迟发性炎症的影响我们将通过确定最佳方案来充分描述 CCR2 拮抗剂治疗的特征。我们将检查放射计划引起的急性和迟发性炎症的剂量和缓解。我们还将描述该策略在年轻和老年动物中的普遍适用性。拮抗剂调节损伤中骨髓源性炎症免疫细胞的释放和募集确定CCR2抑制剂的作用机制将有助于将其作为医学对策。根据 FDA 的动物规则对抗辐射。