CD47/SIRPα通路阻断联合视黄酸治疗子宫内膜异位症的分子机制研究

Endometriosis (EM) incidence and recurrence rates are high, thereby seriously affecting patients’ physical and mental health. However, EM’s pathogenesis is not clear. Peritoneal macrophages play an important role in the EM process, but their phagocytic ability is weakened, and the state of functional differentiation is unclear. In our previous study, we found that large peritoneal macrophage had a great potential to inhibit EM progression, and CD47 expression in ectopic endometrial tissue is elevated. Therefore, we have opened a new research entry point from the perspective of new subtypes of peritoneal macrophages. Macrophage subtype transformation through retinoic acid is performed, thereby enhancing the phagocytic capacity and M1 functional polarization potential of total peritoneal macrophages. In addition, we integrate the frontier hotspots in immunotherapy, explore the possibility of blocking EM based on macrophage immunological checkpoints, and use EM animal models and clinical samples to clarify the changes in the CD47–SIRPα pathway in the EM process. We also study the underlying mechanism of CD47’s evasion of macrophage phagocytosis by CD47-gene-modified cells. Then, we will use antibodies to block this pathway to study its effect on EM progression. Both treatments are based on the regulation of peritoneal macrophages, and we explore the advantages of combination therapy. This project not only deepens the research on the pathogenesis of EM, but also explores a new treatment strategy of EM.

子宫内膜异位症（Endometrisosis，EM）发病率和复发率高，严重影响患者身心健康，但其发病机制不明确。腹腔巨噬细胞在EM进程中发挥重要作用，然而，EM中腹腔巨噬细胞的吞噬能力减弱、且功能分化状态不明确。我们在前期基础中发现大腹腔巨噬细胞具有更强的抑制EM进展的潜力，且异位内膜组织的CD47表达升高。因此，我们从腹腔巨噬细胞新亚型角度开辟新的研究切入点，利用视黄酸诱导巨噬细胞亚型转化，进而增强总腹腔巨噬细胞的吞噬能力和M1功能极化潜力。此外，我们将整合免疫治疗领域的前沿热点，探讨基于巨噬细胞免疫检查点阻断治疗EM的可能性，阐明CD47-SIRPα通路在EM进程中的变化规律，进而明确CD47在逃避巨噬细胞吞噬中的作用机理，利用抗体阻断该通路研究其对EM进程的影响。上述两种治疗方案均基于调控腹腔巨噬细胞，我们将探究联合治疗的优势。本项目既深化EM发病机制研究，又探索EM新治疗策略。

子宫内膜异位症（Endometrisosis，EM）发病率和复发率高，严重影响患者身心健康，但其发病机制不明确。腹腔巨噬细胞在EM进程中发挥重要作用，然而，EM中腹腔巨噬细胞的吞噬能力减弱、且功能分化状态不明确。我们从腹腔巨噬细胞新亚型角度和免疫检查点角度开辟新的研究切入点，明确了CD47-SIRPα信号通路在子宫内膜异位症中的异常表达情况，通过构建敲除和过表达子宫内膜间质细胞，联合动物实验明确了CD47阻断治疗对于EM的治疗效果。基于巨噬细胞亚型的功能差异，发现视黄酸能够诱导腹腔巨噬细胞亚型转化，进而提高整体巨噬细胞的吞噬能力，初步说明视黄酸对于EM具有缓解作用。基于巨噬细胞起源和功能的复杂性，完成了EM的单细胞测序工作，实现了细胞构成图谱构建工作，并筛选出一类巨噬细胞亚群，初步实验提示该类巨噬细胞能够促进EM病程的进展。我们研究进一步深化了巨噬细胞在EM中的作用机制，探索了靶向CD47的免疫治疗效果。单细胞测序结果更是开辟新的研究点。