基于NAD+/SIRT2-NLRP3乙酰化探讨胰岛巨噬细胞介导的β细胞去分化在酒精致糖尿病中的作用及烟酰胺单核苷酸干预机制研究

胰岛β细胞功能减退是酒精致2型糖尿病发病的核心事件，然而酒精诱发β细胞功能减退的具体机制远未阐明。本项目拟以新近发现的β细胞去分化现象为切入点，聚焦于酒精对NAD+/SIRT2-NLRP3蛋白乙酰化这一巨噬细胞NLRP3炎性小体活化通路的靶向调控作用，借助基因过表达、通路阻断等多种分子生物学手段，从动物和细胞、分子水平层层剖析酒精触发胰岛巨噬细胞NLRP3炎性小体活化并介导β细胞去分化的病理生理学意义及潜在机制。在此基础上，选择膳食来源丰富并可靶向补充机体NAD+水平的烟酰胺单核苷酸作为干预物，分析其对酒精触发胰岛巨噬细胞NLRP3炎性小体活化并介导β细胞去分化效应的潜在调控机制及主要作用靶点，从全新的角度揭示其拮抗酒精诱发糖尿病的分子作用机制。本项目的实施不仅有助于进一步阐明酒精致糖尿病发病机制，还将为烟酰胺单核苷酸在酒精相关疾病中的营养干预提供新的思路。

Pancreatic β-cell dysfunction has been proposed as a central mechanism underlying ethanol-induced type 2 diabetes mellitus (T2DM), however, the potential mechanisms by which ethanol triggering β-cell dysfunction remains unclear. Our present project is designed to explore the pathophysiological significance and the potential molecular mechanisms involved in ethanol induced macrophage NLRP3 inflammasome activation and its role in β-cell dedifferentiation. Our research will focus on the ethanol triggered NAD+/SIRT2-NLRP3 acetylation signaling pathway and its role in macrophage NLRP3 inflammasome activation-induced β-cell dedifferentiation, which is realized by the combination of animal and cell experiment with the help of gene-overexpression and pathway blocking and other molecular biology techniques. In addition, nicotinamide mononucleotide is selected as an intervention because it can effectively supplement the ethanol metabolism-consumed NAD+. Clarifying the potential regulatory mechanism of nicotinamide mononucleotide in ethanol-induced β-cell dedifferentiation, would be helpful to reveal the molecular mechanisms of nicotinamide mononucleotide in improving ethanol-induced T2DM from a new perspective. Thus, this project will not only help to further clarify the mechanisms of ethanol-induced T2DM, but also provide new clues and experimental basis for the nutritional intervention of nicotinamide mononucleotide in the ethanol ingestion-related disease.