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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：
10474889
负责人：
Richard J DiPaolo
金额：
$ 71.98万
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/10474889
关键词：
Acute Affect Aftercare Animals Anti-Inflammatory Agents Antineoplastic Agents Atherosclerosis B-Lymphocytes Basophils Blood Circulation Bone Marrow Bone Marrow Involvement Cell Lineage Cells 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 Peritoneal Macrophages Pharmacology 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 base 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 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.

项目摘要目前，需要制定减轻急性和迟发性放射综合症的策略。风险大遭受辐射照射的人口是真实的，而且还在增加。辐射诱发的炎症在诱发辐射毒性中的重要作用。趋化因子信号转导在全身和局部通过调节炎性免疫细胞如炎性单核细胞的流出和募集来调节炎症和T细胞。辐射暴露诱导炎症细胞的募集，并促进全身和局部炎症我们已经观察到，在小鼠中表达趋化因子受体2的基因的缺失促进了抗辐射性CCR2信号传导的药理学抑制减轻小鼠中的急性辐射综合征。此外，接受CCR 2拮抗剂治疗的这些动物没有出现急性辐射的延迟效应暴露（DEARE），如辐射诱发的肺综合征。在本提案中，我们将研究 CCR2抑制剂对辐射诱导的急性和迟发性炎症的影响迟发性辐射损伤我们将充分表征CCR2拮抗剂治疗，确定最佳治疗方案。减轻辐射诱导的急性和延迟炎症的剂量和时间表。我们会研究该策略在年轻和老年动物中的普遍适用性。我们还将描述CCR 2的作用，拮抗剂在调节骨髓源性炎性免疫细胞释放和募集中的作用组织.确定将促进CCR2抑制剂作为医学对策的作用机制根据食品药品管理局的动物条例