GRB14 (Growth factor receptor-bound protein 14) is a member of the GRB7 protein family and functions as an intracellular adaptor protein that regulates multiple signaling pathways through interactions with receptor tyrosine kinases and downstream signaling molecules. GRB14 is an important negative regulator of insulin receptor signaling by binding to the insulin receptor and inhibiting its kinase activity, thereby contributing to the regulation of glucose and lipid metabolic homeostasis. Studies have shown that abnormal GRB14 expression is associated with insulin resistance, type 2 diabetes (T2D), hypertriglyceridemia, metabolic dysfunction-associated steatotic liver disease (MASLD), and other metabolic disorders ^[1-4]. In addition, dysregulated GRB14 expression has been implicated in the development of various cancers and may regulate malignant biological processes, including tumor cell proliferation, migration, and invasion ^[5-6]. The huGRB14 humanized mouse model was generated using gene-editing technology by replacing the mouse Grb14 gene sequence from the start codon to the stop codon with the corresponding human GRB14 gene sequence from the start codon to the stop codon. This model can be used for mechanistic studies of metabolic disorders, including hypertriglyceridemia, type 2 diabetes (T2D), and metabolic dysfunction-associated steatotic liver disease (MASLD), as well as investigations into GRB14-associated tumor development. Furthermore, this model may facilitate the evaluation of potential glucose-lowering, lipid-modulating, and anti-tumor therapeutic strategies targeting human GRB14. It can also serve as an immunization tool mouse model for the generation of human GRB14-specific monoclonal antibodies.

Lif is located on chromosome 11 of mice. Nuclease Technology will be used to design sgRNA; Lif knockout mice will be obtained by applying high-throughput electroporation of fertilized eggs. After sexual maturity, sperm were collected for cryopreservation.