SD-hGHR Rats

Catalog Number: CR008

Strain Name: SD-Ghrem1(hGHR)/Cya

Genetic Background: Sprague-Dawley

Reproduction: Homozygote x Homozygote

 

Strain Description

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.

SD-hGHR 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 SD-hGHR 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.

 

Strain Strategy


Figure 1. Gene editing strategy for SD-hGHR rats. The partial coding sequence of exon 2 and intron 2 of the rat Ghr gene was replaced with a sequence containing part of the human GHR gene "Chimeric Human GHR CDS-Human GHR 3'UTR-3xSV40 pA". The chimeric human GHR CDS consists of 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.

 

Application

  • GHR-targeted drug screening, development, and evaluation;
  • Research on the pathological mechanisms and therapeutic approaches of endocrine diseases and specific cancers.

 

References
[1]Dehkhoda F, Lee CMM, Medina J, Brooks AJ. The Growth Hormone Receptor: Mechanism of Receptor Activation, Cell Signaling, and Physiological Aspects. Front Endocrinol. 2018 Feb 13;9:35.
[2]Guevara-Aguirre J, Rosenbloom AL. Obesity, diabetes and cancer: insight into the relationship from a cohort with growth hormone receptor deficiency. Diabetologia. 2015 Jan;58(1):37-42.
[3]Chhabra Y, Lee CMM, Müller AF, Brooks AJ. GHR signalling: Receptor activation and degradation mechanisms. Mol Cell Endocrinol. 2021 Jan 15;520:111075. doi:10.1016/j.mce.2020.111075
[4]Unterberger CJ, McIlwain SJ, Tsourkas PK, Maklakova VI, Prince JL, Onesti A, Hu R, Kopchick JJ, Swanson SM, Marker PC. Conditional gene regulation models demonstrate a pro-proliferative role for growth hormone receptor in prostate cancer. The Prostate. 2023;83:416 - 429.