TSP4促巨噬细胞吞噬作用抑制恶性间皮瘤进展的机制研究

恶性间皮瘤（MM）中巨噬细胞吞噬功能低下是MM进展的重要原因。如何增强巨噬细胞吞噬作用是MM研究的重要科学问题，但其机制尚未阐明。我们前期研究发现，TSP4在MM中表达显著降低，且与预后差相关。进一步研究显示，TSP4能促进巨噬细胞的吞噬作用。结构预测提示TSP4可结合CD47。而MM细胞CD47和巨噬细胞SIRPα结合后，可抑制巨噬细胞吞噬。因此申请人推测TSP4通过竞争性结合CD47，阻断CD47-SIRPα介导的“Don‘t eat me”信号，进而增强巨噬细胞吞噬，抑制MM进展。本课题在前期研究基础上，将以巨噬细胞吞噬功能为研究切入点，聚焦CD47-SIRPα信号，采用人体标本及体内外实验，多角度多模型分析：TSP4对MM的影响；TSP4促进巨噬细胞吞噬的机制；筛选并评价小分子多肽抑制MM进展的作用。本项目将从新的角度阐明MM发病机制，为MM的诊治提供新的理论依据及干预靶点。

The phagocytic dysfunction of macrophages in malignant mesothelioma (MM) is an important reason for the progression of MM. How to enhance macrophage phagocytosis is an important scientific problem in MM research. But the mechanism has not yet been elucidated. Our previous study found that the expression of TSP4 in MM was significantly decreased and correlated with poor prognosis. Further studies have shown that TSP4 can promote the phagocytosis of macrophages. Structural prediction suggested that TSP4 could bind to CD47. However, while CD47 of MM cell was binding to SIRPα of macrophage, the phagocytosis of macrophage was inhibited. Therefore, the applicant speculated that TSP4 could competitively bind CD47 to block the CD47-SIRPα mediated "Don 't eat me" signal, so as to enhance macrophage phagocytosis and inhibit MM progression. On the basis of previous research, this project will focus on the phagocytic function of macrophages as the research entry point, and focus on CD47-SIRPα signal. It will use human specimens，in vivo and in vitro experiments via multi-angle and multi-model analysis: the influence of TSP4 on MM; Mechanism of promoting macrophage phagocytosis by TSP4; To screen and evaluate the inhibitory effect of small molecule polypeptides on MM progression. This project will elucidate the pathogenesis of MM from a new perspective and provide a new theoretical basis and intervention target for the diagnosis and treatment of MM.