联合OCT基于Galectin-3为靶点的褪黑素促TFEB去乙酰化诱导巨噬细胞自噬稳定动脉粥样硬化易损斑块的机制研究

Atherosclerotic cardiovascular disease has become the leading cause of deathworldwide. Acute cardiovascular events caused by atherosclerosis （AS）vulnerableplaques are a clinically difficult problem, and the current clinical therapy has some limitations. Galectin-3 (Gal-3) as a novel vascular inflammatory factor plays an important role in AS. Melatonin (MT) is an endogenous biological small molecule. The results of RNAseq analysis in our group confirmed that the expression of Gal-3 gene was down-regulated in MT-treated macrophages. Our previous results suggested that MT enhanced deacetylation level of TFEB （transcription factor EB, TFEB) and promoted macrophages autophagy.Based on these results, a scientific hypothesis is proposed: MT activates the NAD+ synthesis pathway and the deacetylation of TFEB and Nrf2 (Nuclear factor-erythroid 2-related factor 2) by regulating Gal-3, thereby inducing macrophages autophagy and futherstablizing AS vulnerable plaques. It is proposed to use a variety of macrophage, knockout mice and rabbit AS model, combined with optical coherence tomography (OCT) to achieve in situ detection of macrophages and vulnerable plaques, study the molecular regulation mechanism of MT targeted on Gal-3 in AS macrophage autophagy and related inflammatory pathways ,which provides the new target for AS clinical treatment.

动脉粥样硬化性心血管疾病已成为世界范围内主要致死原因，动脉粥样硬化（Atherosclerosis，AS）易损斑块引起的急性心血管事件是临床棘手问题，治疗存在局限性。半乳糖凝集素-3（Galectin-3，Gal-3）作为新型血管炎症因子在AS中发挥重要作用。褪黑素（Melatonin，MT）是内源性生物小分子，前期RNAseq结果证实经MT处理的巨噬细胞，Gal-3基因表达下调。实验结果提示MT提高转录因子EB（TFEB）去乙酰化水平，促进巨噬细胞自噬。提出科学假设：MT通过调控Gal-3激活NAD+合成通路，促进巨噬细胞TFEB及核因子E-2相关因子2去乙酰化 ，诱导巨噬细胞自噬，稳定AS易损斑块。拟采用多种巨噬细胞、基因敲除小鼠和兔AS模型，联合光学相干断层成像技术，实现巨噬细胞和易损斑块原位检测，研究MT作用靶点Gal-3在AS巨噬细胞自噬的调控机制，为AS临床干预提供新靶点。

动脉粥样硬化性心血管疾病已成为世界范围内主要致死原因，动脉粥样硬化（Atherosclerosis，AS）易损斑块引起的急性心血管事件是临床棘手问题，治疗存在局限性。半乳糖凝集素-3（Galectin-3，Gal-3）作为新型血管炎症因子在AS中发挥重要作用。本项目证实褪黑素（Melatonin，MT）通过调控Gal-3，促进巨噬细胞TFEB及Nrf2去乙酰化，诱导巨噬细胞自噬，降低炎症因子产生，抑制氧化应激，稳定AS易损斑块，为AS临床干预提供新靶点。.本项目申请国家实用新型专利2项，已授权1项。发表SCI文章6篇，中文核心3篇，其中IF≥5.0 4篇，5.0≥IF≥4.0 2篇。项目主持人获2020黑龙江省科学技术奖（自然科学奖）二等奖（排名第一），获黑龙江省杰出青年基金、哈尔滨医科大学三级教授、哈尔滨医科大学星联教授。项目组毕业博士研究生1名，硕士研究生3名。项目主持人在国内做专题报告8次。