糖尿病的发生发展与胰岛稳态失衡密切相关，GPCR对胰岛稳态有重要的调控作用。然而，GPCR超家族中粘附类受体在胰岛中的功能还知之甚少。我们的前期研究发现，糖尿病病人胰岛和糖尿病小鼠模型中粘附类受体GPR126表达水平显著改变，GPR126组织特异性敲除小鼠糖代谢紊乱。申请人还发现GPR126在胰岛中潜在的内源性新配体并初步获得激活GPR126偏好性信号途径的纳米抗体。在此基础上，申请人拟利用胰岛δ细胞及β细胞特异性GPR126基因敲除小鼠，纳米抗体和Aptamer等筛选技术，结合国际上GPCR偏好性途径的功能以及胰岛环路对胰岛稳态的调节作用等研究热点，阐明GPR126对胰岛稳态维持的作用，探索GPR126下游偏好性信号途径在胰岛中的精确调节机制；发展并评估GPR126偏好性配体对胰岛稳态失衡和糖代谢改善的干预能力。本项目不仅拓展对胰岛中粘附类受体功能的认识，还可为糖尿病治疗提供新思路。

The impairment of the pancreatic islet homeostasis is highly associated with the diabetes development. The transmembrane receptor G protein coupled receptor(GPCR) superfamily was known to play important roles in regulation of the pancreatic islet homeostasis. However, the regulatory roles of the adhesion GPCRs, one of the five families of GPCR superfamily, still largely remain elusive. Recently, through examination of the clinical samples from diabetes patients and diabetic mouse models, we found a significant decrease of the GPR126 expression in islets of diabetic patients or mouse models, compared to heathy people or control mouse respectively. Moreover, we have identified a potential new endogenous ligand of the GPR126 in pancreatic islets, which negatively regulated GPR126 function and promoted GPR126 degradation. The mouse model of the pancreatic β or δ cell GPR126 deficient mice caused metabolic disorder. Through immunization of lama with the purified GPR126 protein, two nanobodies were found to selective activate GPR126 biased signaling through GPR126 with low nanomolar concentration. In this proposal, the applicant will utilize the specific knockout model of GPR126 in pancreatic δ or β cells, combining the physiological and cell biology approaches, focusing on biased signaling downstream of GPR126, to elucidate the function and underlying mechanism of the GPR126 in regulation of pancreatic islet homeostasis. Moreover, the applicant will use the in vitro receptor complex reconstitution, nanobody screening or SELEX technique, to identify the biased ligand of GPR126, and probing its ability in improving the glucose disorder in mouse models. This project will not only broaden the knowledge of the function of adhesion GPCR in regulation of pancreatic islet homeostasis, but will also provide new clue to treat diabetes.