游离脂肪酸受体（FFAR2）通过抑制单核/巨噬细胞功能改善胰岛炎症浸润的作用机制研究

Free fatty acid receptors (FFARs) are G protein-coupled receptors which specifically bind free fatty acids, and closely link to series of intracellular signals and physiological processes. FFAR2 is highly expressed in peripheral blood mononuclear cells, bone marrow, spleen, intestine and fat tissues. Macrophages account for the majority of infiltrated immunocytes at the early stage of insulitis in diabetes. Here, we try to test the hypothesis that activation of FFAR2 could reduce the inflammatory response mediated by macrophages, decrease inflammatory infiltration of islets, and block the damage to islet β cell. The mechanism of the macrophage apoptosis mediated by FFAR2 activation through ERK pathway is planned to be studied both in vivo and in vitro. Preliminary clinical research will be carried out to study the role of acetate, the natural ligand of FFAR2, which might play a role in diabetes adjuvant therapy. Above all, the current proposal hopes to provide supports from bench to bed-side for FFAR2 as a potential new drug target in the treatment of autoimmune diabetes.

游离脂肪酸受体（Free Fat Acid Receptor，FFAR）是一类能特异结合游离脂肪酸的G蛋白偶联受体，同体内一系列细胞内信号及生理过程有密切关系。 FFAR2又名GPR43，在外周血单个核细胞、骨髓、脾脏、肠道和脂肪等组织均有表达。目前，关于FFAR2的研究主要集中在免疫、肠炎和脂肪分化领域。本课题在前期工作基础上，以单核/巨噬细胞为研究对象，将在分子、细胞和动物模型水平证明游离脂肪酸受体（FFAR2）激活后可抑制单核/巨噬细胞介导的炎症反应及其在胰腺组织内的浸润，进而减少胰岛β细胞凋亡，降低胰岛炎症水平的假说；进一步深入、全面地诠释FFAR2激活通过ERK通路介导巨噬细胞凋亡的作用机制；并通过临床研究，初步探讨FFAR2天然配体醋酸盐对糖尿病的辅助治疗功效。最终，拟在自身免疫性糖尿病治疗领域，为FFAR2配体的成药性提供有力佐证。

游离脂肪酸受体（Free Fat Acid Receptor，FFAR）是一类能特异结合游离脂肪酸的G蛋白偶联受体，同体内一系列细胞内信号及生理过程有密切关系。 FFAR2又名GPR43，在外周血单个核细胞、骨髓、脾脏、肠道和脂肪等组织均有表达。本课题在前期工作基础上，以单核/巨噬细胞为研究对象，在分子、细胞和动物模型水平证明游离脂肪酸受体（FFAR2）激活后可抑制单核/巨噬细胞介导的炎症反应及其在胰腺组织内的浸润，进而减少胰岛β细胞凋亡，降低胰岛炎症水平的假说；进一步深入、全面地诠释 FFAR2 激活通过 ERK 通路介导巨噬细胞凋亡的作用机制；并通过临床研究，初步探讨了 FFAR2 天然配体醋酸盐对糖尿病的辅助治疗功效，为 FFAR2 配体在自身免疫性糖尿病治疗领域的成药性提供有力佐证。