Gpr65-flox Mouse

Gpr65, a G-protein coupled receptor, is a proton-sensing receptor. It is involved in regulating multiple pathophysiological processes through various signaling pathways such as Gαq-Ca2+-JNK/NF-κB, cAMP-PKA-C-Raf-ERK1/2-LKB1, and cAMP/PKA/CREB [1,2,5]. It plays a significant role in maintaining tissue homeostasis and is associated with multiple diseases [1-5,7-10]. Genetic models, especially knockout (KO) and conditional knockout (CKO) mouse models, have been crucial in understanding its functions.

In liver fibrosis, Gpr65-deficient mice showed alleviated liver inflammation, injury, and fibrosis induced by bile duct ligation or carbon tetrachloride treatment. Gpr65 in hepatic macrophages was upregulated in fibrotic livers, and its knockout's protective effect was mainly mediated by bone marrow-derived macrophages. Mechanistically, Gpr65 regulated the activation of hepatic stellate cells and damage of hepatocytes via the Gαq-Ca2+-JNK/NF-κB and Gαq-Ca2+-MLK3-MKK7-JNK pathways [1].

In intestinal mucosal inflammation, conditional knockout of Gpr65 in CD4+ T cells ameliorated trinitrobenzene sulfonic acid-induced acute murine colitis and chronic colitis in Rag1-/-mice. Gpr65 promoted Th1 and Th17 cell differentiation by downregulating NUAK2 [2].

In obesity-associated cancers like colorectal and hepatocellular carcinoma, macrophage-specific Gpr65 promoted tumor growth [3].

In the gut, Gpr65 deletion in intestinal epithelial cells abrogated antimicrobial programs, making mice prone to colitis [4].

In glioma, Gpr65 on tumor-associated macrophages promoted tumor progression by sensing lactate and releasing HMGB1 [5].

In trophoblast cells, overexpression of Gpr65 inhibited adhesion, migration, and invasion under acidic conditions [6].

In glioma, Gpr65 was identified as a hub gene in M2 macrophage-related modules, and its inhibition reduced macrophage polarization [7].

Delayed treatment with the Gpr65 agonist BTB09089 promoted neurorehabilitation after ischemic stroke in wild-type but not Gpr65-/-mice [8].

In B-cell acute lymphoblastic leukemia, Gpr65 inactivation in tumor cells led to CAR T-cell resistance [9].

In conclusion, Gpr65 is a key regulator in multiple biological processes. Studies using KO and CKO mouse models have revealed its role in liver fibrosis, intestinal inflammation, obesity-associated cancers, gut mucosal homeostasis, glioma progression, trophoblast cell function, neurorehabilitation after stroke, and CAR T-cell therapy response in leukemia. These findings provide potential therapeutic targets for related diseases.