鱼油来源的顺式棕榈油酸调节肠道稳态抗急性移植物抗宿主病（aGVHD）的作用及机制研究

Acute graft-versus-host disease (aGVHD) has limited therapeutic options, and thus restricts the development of allogeneic hematopoietic stem-cell transplantation (allo-HSCT). Recent insights into intestinal homeostasis and uncovering of new pathways have greatly reconciled our understanding of aGVHD pathophysiology. Palmitoleic acid (POA) is a new healthy fatty acid and helps maintain intestinal homeostasis. It has shown tissue repair, anti-inflammatory, antibacterial and immunosuppressive effects when used to treat various diseases, which may be beneficial to mitigate aGVHD. In our previous studies, the cis isomer of POA (cis-POA) was successful extracted from fish oil and highly purified. Moreover, we confirmed that cis-POA can suppress T cell proliferation and activation in a concentration-dependent manner. Based on the previous results, we hypothesized that cis-POA have the therapeutic potential on aGVHD by regulating intestinal homeostasis to promote the tissue repair, organ reconstruction, immune tolerance and microbial remodeling. In order to verify our hypothesis, this project intends to investigate the anti-aGVHD effect of cis-POA and the underlying signal transduction pathways participating in intestinal homeostasis, using our established technologies including in vitro cell culture studies, ex vivo organoid/enteroid model and in vivo animal models. This project may provide a new and promising treatment approach for aGVHD, which have not yet been reported.

急性移植物抗宿主病（aGVHD）制约了移植的应用和发展，临床上治疗方法有限，研究发现aGVHD的病生机制与肠道稳态相关。天然棕榈油酸（POA）可调节肠道微生态，且在不同疾病的治疗中展现组织修复、抗炎抗菌和免疫抑制等，可能有助于应对aGVHD的发生发展。项目组前期从鱼油中分离制备高纯度的POA顺式异构体（cis-POA），并证实cis-POA有效抑制T细胞的体外增殖活化，预示cis-POA抗aGVHD的潜能。基于前期研究提出假说：cis-POA通过调节肠道稳态，促进aGVHD靶器官组织修复、功能重建、免疫耐受和微生态重塑，实现aGVHD的防治。为此，本项目拟已建立的体外免疫反应体系、多能干细胞技术和aGVHD小鼠模型，在细胞学、类器官模型和动物实验三个层面阐明cis-POA的抗aGVHD作用，并探讨其调节肠道稳态和信号传导通路的作用机制。为治疗aGVHD提供新策略，应用前景好，尚无文献报道。

急性移植物抗宿主病（aGVHD）制约了造血干细胞移植的应用和发展，临床上治疗方法有限，本项目从鱼油中分离制备高纯度的POA顺式异构体（cis-POA），并开发了POA的体外和体内检测方法，同时研究了POA在大鼠体内的代谢动力学相关参数。证实cis-POA对体外淋巴细胞增殖活化的影响。通过构建动物模型，证明cis-POA在治疗aGVHD中的积极作用，包括生存情况、疾病转归、靶器官组织修复、免疫耐受情况，同时在动物模型中验证了cis-POA的治疗作用不干扰移植物抗白血病（GVL）效应。通过深入动物实验及相关体外细胞研究，从肠道稳态及相关信号传导通路的重建探讨 cis-POA 的作用机制，为治疗aGVHD提供新策略，应用前景好。