The GPR75 gene encodes a transmembrane protein belonging to the G protein-coupled receptor (GPCR) family. This receptor is primarily expressed in the brain, particularly enriched in the cilia of hypothalamic neurons that regulate appetite. It couples with Gαq proteins to activate downstream signaling pathways (such as MAPK, NF-κB, etc.), participating in the regulation of energy balance, feeding behavior, and fat metabolism ^[1][2]. The encoded protein comprises 540 amino acids with a typical 7-transmembrane structure. Upon binding with ligands like 20-hydroxyeicosatetraenoic acid (20-HETE), it can trigger physiological effects such as inflammation, vasoconstriction, and lipid accumulation ^[2][3]. Research has found that loss-of-function or mutations in GPR75 (e.g., the L144P variant) can significantly reduce body weight and fat mass, resist high-fat diet-induced obesity and non-alcoholic fatty liver disease (NAFLD), and improve insulin sensitivity ^[1][3][4]. Furthermore, GPR75 mediates 20-HETE-induced cardiomyocyte apoptosis in the cardiovascular system, which is associated with hypertension and endothelial dysfunction ^[2][3]. In cancer, GPR75 may promote cachexia progression by regulating white adipose tissue browning ^[5]. Whole-exome sequencing has revealed that rare variants in GPR75 are closely related to low BMI and reduced obesity risk in humans, making it a promising therapeutic target for obesity, metabolic syndrome, and cardiovascular diseases ^[3]. The huGPR75(2) mouse is a humanized model generated through gene editing technology, in which part of the mouse Gpr75 gene sequence is replaced in situ with the human GPR75 gene sequence. Homozygous huGPR75(2) mice are viable and fertile. This model can be used to study the pathological mechanisms and therapeutic interventions for obesity, metabolic diseases, and cardiovascular diseases, as well as for screening, developing, and evaluating the safety of GPR75-targeted drugs.

The GPR75 gene encodes a transmembrane protein belonging to the G protein-coupled receptor (GPCR) family. This receptor is primarily expressed in the brain, particularly enriched in the cilia of hypothalamic neurons that regulate appetite. It couples with Gαq proteins to activate downstream signaling pathways (such as MAPK, NF-κB, etc.), participating in the regulation of energy balance, feeding behavior, and fat metabolism ^[1][2]. The encoded protein comprises 540 amino acids with a typical 7-transmembrane structure. Upon binding with ligands like 20-hydroxyeicosatetraenoic acid (20-HETE), it can trigger physiological effects such as inflammation, vasoconstriction, and lipid accumulation ^[2][3]. Research has found that loss-of-function or mutations in GPR75 (e.g., the L144P variant) can significantly reduce body weight and fat mass, resist high-fat diet-induced obesity and non-alcoholic fatty liver disease (NAFLD), and improve insulin sensitivity ^[1][3][4]. Furthermore, GPR75 mediates 20-HETE-induced cardiomyocyte apoptosis in the cardiovascular system, which is associated with hypertension and endothelial dysfunction ^[2][3]. In cancer, GPR75 may promote cachexia progression by regulating white adipose tissue browning [5]. Whole-exome sequencing has revealed that rare variants in GPR75 are closely related to low BMI and reduced obesity risk in humans, making it a promising therapeutic target for obesity, metabolic syndrome, and cardiovascular diseases ^[3]. The B6-hGPR75 (1) mouse is a humanized model generated through gene editing technology, in which part of the mouse Gpr75 gene sequence is replaced in situ with the human GPR75 gene sequence. Homozygous B6-hGPR75 (1) mice are viable and fertile. This model can be used to study the pathological mechanisms and therapeutic interventions for obesity, metabolic diseases, and cardiovascular diseases, as well as for screening, developing, and evaluating the safety of GPR75-targeted drugs.

Trp53rka is located on chromosome 2 of mice. SgRNA and ssDNA will be designed using Nuclease Technology; Trp53rka conditional knockout mice will be obtained by high-throughput electroporation of fertilized eggs. After sexual maturity, sperm will be collected for cryopreservation.