课题基金 / 基金详情

项目摘要

项目成果

Bishuang Cai的其他基金

相似基金

相关文献

中文摘要
翻译
摘要 随着吞噬细胞主动清除凋亡细胞(ACS),细胞凋亡持续发生。 泡细胞,称为“泡细胞吞噬作用”,以维持组织的动态平衡。当气泡吞噬功能出现缺陷时, 未清除的急性冠脉综合征经历凋亡后的坏死并释放免疫原表位和促炎因子 介质,这会导致慢性炎症性疾病。我们最近的研究揭示了一个新的角色 泡腾作用加速组织修复,因为它通过诱导生物合成促进炎症消退 能阻止炎症反应的专门的促分解介质(SPM)。因此,了解如何 泡腾作用的成功进行至关重要。人们已经了解了很多关于 AC识别和摄取的机制,但传出细胞如何降解ACS和处理代谢货物, 例如,从AC消化中释放的胆固醇,目前还不完全清楚。此外,虽然泡沫化和 内吞作用有共同的特征,如涉及细胞骨架重排和细胞内转运。 囊泡膜结合的货物,泡泡细胞是否劫持内吞机制来处理AC- 衍生货物仍不确定。在我们未发表的结果中,我们发现决议蛋白d1(Rvd1),a 二十二碳六烯酸(DHA)衍生的SPM,增强了含AC隔间的酸化 LC_3相关吞噬细胞吞噬(LAP)介导的身体的主要特征 退化。因为我们最近的研究表明,胞吐受体MerTK的激活是必需的 对于RvD1的生物合成,这些结果表明MerTK-RvD1信号在LAP介导的AC中发挥了新的作用 退化。为了研究关键的内吞调节因子--C-末端Eps15同源结构域(EHD) 我们分析了由EHD1、EHD2、EHD3和EHD4-组成的蛋白质参与泡腾相关的事件。 来自动脉粥样硬化病变的单细胞RNA测序(scRNA-seq)数据集,其中许多细胞经历了 发现EHD蛋白具有异质性表达,EHD1和EHD4高表达 巨噬细胞中的专业泡沫状细胞。我们进一步发现,EHD1增强了细胞表面的水平 巨噬细胞胞吐过程中胆固醇外流转运蛋白ABCA1的表达,提示EHD1- ABCA1介导的胞内转运可能在清除体内释放的过量游离胆固醇中发挥作用 消化的急性冠脉综合征。在这里,我们建议结合细胞生物学、生物化学、小鼠遗传学和 功能基因组学研究MerTK-RvD1信号在LAP和EHD中的功能和机制 泡饮相关事件中的蛋白质,包括维持细胞胆固醇稳态和控制 MerTK的胞内转运。我们还将进行无偏见的全基因组CRISPR筛查,以识别新的 巨噬细胞接受急性冠脉综合征时细胞表面MerTK水平的调节。放在一起,理解 泡沫化作用的这些方面将阐明关键的生理和病理生理过程,并提示 由缺陷泡泡细胞增多症引起的疾病的新治疗策略。
英文摘要
ABSTRACT Apoptosis happens continuously along with the active clearance of apoptotic cells (ACs) by phagocytes or efferocytes, termed “efferocytosis”, to maintain tissue homeostasis. When efferocytosis becomes defective, uncleared ACs undergo post-apoptotic necrosis and release immunogenic epitopes and pro-inflammatory mediators, which leads to chronic inflammatory diseases. Our recent studies revealed a novel role of efferocytosis in accelerating tissue repair as it promotes inflammation resolution by inducing the biosynthesis of specialized pro-resolving mediators (SPMs) that stop inflammatory responses. Therefore, understanding how efferocytosis is successfully carried out is of paramount importance. Much has been learned about the mechanisms of AC recognition and uptake, but how efferocytes degrade ACs and process the metabolic cargo, e.g., cholesterol released from AC digestion, is incompletely understood. Moreover, although efferocytosis and endocytosis share common features, such as involving cytoskeleton rearrangement and intracellular transport of vesicular membrane-bound cargoes, whether efferocytes hijack the endocytic machinery to process AC- derived cargo remains uncertain. In our unpublished results, we found that resolvin D1 (RvD1), a docosahexaenoic acid (DHA)–derived SPM, enhanced the acidification of the AC-containing compartments (efferosomes) and LC3-II lipidation, key features in LC3-associated phagocytosis (LAP)-mediated corpse degradation. As our recent study showed that the activation of MerTK, the efferocytosis receptor, was required for RvD1 biosynthesis, these results indicate a novel role of MerTK-RvD1 signaling in LAP-mediated AC degradation. To study whether the key endocytic regulators—the C-terminal Eps15 Homology Domain (EHD) proteins comprising EHD1, EHD2, EHD3, and EHD4—are involved in efferocytosis-related events, we analyzed a single-cell RNA-sequencing (scRNA-seq) dataset from atherosclerotic lesions where a lot of cells undergo apoptosis and found that EHD proteins had heterogeneous expression with high expression of EHD1 and EHD4 in macrophages, the professional efferocytes. We further found that EHD1 enhanced the cell surface levels of the cholesterol efflux transport protein ABCA1 in macrophages during efferocytosis, which indicates that EHD1- mediated endocytic trafficking of ABCA1 may play a role in removing the excess free cholesterol released from digested ACs. Here, we propose to combine approaches in cell biology, biochemistry, mouse genetics, and functional genomics to determine the function and mechanisms of MerTK-RvD1 signaling in LAP and EHD proteins in efferocytosis-related events including maintaining cellular cholesterol homeostasis and controlling endocytic trafficking of MerTK. We will also perform unbiased genome-wide CRISPR screening to identify novel regulators of MerTK levels on the cell surface where macrophages receive ACs. Taken together, understanding these aspects of efferocytosis will shed light on key physiological and pathophysiological processes and suggest novel therapeutic strategies for diseases driven by defective efferocytosis.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Disturbed Crosstalk between Cholesterol Homeostasis and Inflammation Resolution in NASH
EHD1-mediated Inflammation and Resolution in Atherosclerosis
Efferocytosis meets endocytosis
MerTK in NASH-related liver fibrosis
海外基金