HuR调控的衰老相关代谢紊乱对血管炎症与动脉粥样硬化的影响机制

衰老相关代谢紊乱增高血管炎症与动脉粥样硬化（AS）的发生风险，但其作用机制不明。前期研究发现，肝细胞HuR敲除降低ATP合成与脂质转运，上调血清血小板活性标志物及SASP样因子水平；增龄小鼠血小板及激活的血小板HuR水平及其与靶标mRNA（编码SASP与能量代谢因子）的结合增强，这些靶标在血小板及血清上调；血小板激活延长TNFα与CCL5 mRNA半衰期；HuR促进IL-1 mRNA加工；血小板HuR缺失小鼠血清SASP水平呈降低趋势。据此，我们假设：HuR直接或间接通过肝脏代谢调控血小板能量代谢与SASP样因子合成分泌，进而通过血行SASP影响衰老相关血管炎症与AS。本课题拟在分子、血小板、血小板-白细胞/内皮互作、肝脏-血小板/内皮互作等层次对这一假说进行验证，筛选特定标志物并尝试针对HuR的干预研究。预期将为解析血管衰老相关病变的代谢与炎症基础乃至防治提供实验依据。

Aging-related metabolism dysfunction increases the occurrence risk of vascular inflammation and atherosclerosis (AS), but the mechanisms underlying remain to be studied. Preliminary results revealed that hepatocyte-specific HuR knockout reduced liver ATP synthesis and lipid transport, increased liver lipid accumulation as well as the levels of serum SASP-like factors and the biomarkers for the activity of platelets; The interaction of HuR with its target mRNAs (encoding factors of SASP and energy metabolism) enhanced in activated platelets and in platelets from aged mice, accompanying with elevation of these factors in platelets and serum; activation of platelets extended the half-lives of TNFα and CCL5 mRNAs; HuR could regulate the processing of IL-1 mRNA；Knockout of HuR in platelets tended to reduce the levels of SASP-like factors in the serum. Based on these findings, we hypothesize that HuR regulates energy metabolism as well as SASP production and secretion of platelets in the levels of post-transcriptional regulation or achieving these regulations in platelets by regulating liver metabolism, in turn influencing aging-related vascular inflammation and atherosclerosis. The present study will set out to validate this hypothesis by studies in the levels of molecules, platelets, liver, interaction between platelet and leukocyte or endothelial cells, interaction between liver and platelets, and interaction between liver and vascular endothelium. The biomarkers for aging-related vascular inflammation and atherosclerosis as well as experimental intervention targeting HuR will be also studied. The anticipated results will provide experimental evidence for revealing the mechanisms underlying the dysfunction of metabolism and SASP in aging-related vascular disorders and for treatment and prevention of these disorders.