hGHR(SD) Rat

The GHR gene encodes the growth hormone receptor (GHR), a type I transmembrane glycoprotein of the cytokine receptor family, serving as the primary receptor for growth hormone (GH) ^[1]. GHR is broadly expressed across various tissues, including liver, bone, muscle, adipose tissue, and immune cells, with particularly high expression in the liver ^[2]. The extracellular domain of GHR contains the GH-binding domain, while the intracellular domain initiates signal transduction, albeit lacking intrinsic tyrosine kinase activity. Upon GH binding to the extracellular domain, GHR dimerization occurs, activating the associated tyrosine kinase JAK2. This, in turn, engages multiple signaling pathways, including JAK-STAT, MAPK/ERK, and PI3K/AKT, which modulate diverse biological processes such as cell growth, differentiation, metabolism, and apoptosis ^[1]. Mutations in the GHR gene are implicated in various disease states. For instance, inactivating mutations are the principal cause of Laron syndrome, resulting in GH insensitivity and severe growth retardation ^[3]. Conversely, gain-of-function mutations, while less frequent, may contribute to the development of certain cancers ^[4]. Consequently, GHR and its associated signaling pathways remain a focus of active research in endocrine disorders and cancer therapeutics.

hGHR(SD) rats are a humanized model generated using gene editing technology, in which the chimeric human GHR CDS encoding the human-rat chimeric GHR protein and its downstream human 3’UTR sequence were integrated into the rat GHR gene locus. In this model, the chimeric human GHR CDS is composed of the following sequences: the sequence encoding the signal peptide and extracellular domain of the human GHR protein, and the sequence encoding the transmembrane and intracellular domains of the rat GHR protein. Homozygous hGHR(SD) rats are viable and fertile, and can be used for studying the pathological mechanisms and therapeutic approaches for endocrine diseases and specific cancers, as well as for the screening, research and development, and preclinical efficacy and safety evaluation of GHR-targeted drugs.

Primate growth hormones (GH) can activate both primate and non-primate somatotropic receptors (GH receptors), whereas non-primate GHs fail to activate primate GH receptors. Previous studies have suggested that the interaction between Asp171 of human GH and Arg43 of the receptor generates an attractive ionic interaction, which serves as one of the important structural bases for determining species-specific recognition and signal activation of GH-GHR ^[5]. Homozygous hGHR(SD) rats exhibited significantly impaired growth hormone (GH) signaling and presented a typical growth hormone deficiency (GHD) phenotype.