BALB/c-hIGF1R Mice

Catalog Number: C001624

Strain Name: BALB/cAnCya-lgf1r^em1(hIGF1R)/Cya

Genetic Background: BALB/cAnCya

Reproduction: Homozygote x Homozygote

Strain Description

The Insulin-like Growth Factor 1 Receptor (IGF-1R), encoded by the IGF1R gene, is a receptor tyrosine kinase expressed in most tissues and cells. Its expression is developmentally regulated and influenced by nutrition, hormones, and intracellular factors, with high expression during growth and development, declining in adulthood ^[1]. The IGF1R protein is a heterotetramer (α2β2) of α and β subunits derived from a precursor protein, forming transmembrane αβ chains. The α chain is located extracellularly, while the β chain spans the cell membrane and is responsible for intracellular signal transduction after ligand stimulation. IGF1R binds Insulin-like Growth Factor-1 (IGF-1) with high affinity, mediating IGF-1's growth-promoting effects and regulating cell growth, differentiation, survival, and metabolism ^[1-4], and IGF1R defects are linked to growth retardation and diabetes ^[2-4]. Furthermore, IGF1R overexpression in tumors promotes proliferation, invasion, and metastasis, making it a cancer therapy target ^[3]. In thyroid eye disease (TED), an autoimmune disorder, activating IGF1R antibodies can be detected. IGF1R is overexpressed in T cells, B cells, and orbital fibroblasts of patients, forming a signal transduction complex with the thyroid-stimulating hormone receptor, thereby enhancing the effect of thyroid-stimulating hormone ^[5]. Therefore, Targeting IGF1R to inhibit thyroid-stimulating hormone action is a therapeutic strategy for TED, improving exophthalmos ^[6].

BALB/c-hIGF1R mice are humanized models generated using gene editing technology by integrating the protein-coding sequence (CDS) encoding the extracellular domain of human IGF1R protein and the intracellular domain of mouse IGF1R protein into the mouse Igf1r gene locus, while retaining the endogenous gene sequence encoding the signal peptide of mouse IGF1R protein (aa.1-30). Homozygous BALB/c-hIGF1R mice are viable and fertile, and can be used for studying the pathological mechanisms and treatments of growth retardation, diabetes, and cancer, as well as for screening, developing, and preclinical efficacy and safety evaluation of IGF1R-targeted drugs.

Strain Strategy

Figure 1. Gene editing strategy for BALB/c-hIGF1R mice. Part of exon 1 coding region and part of intron 1 of the mouse Igf1r gene were replaced by the Human IGF1R CDS (aa.31-935)-Mouse Igf1r CDS (aa.937-1373)-WPRE-BGH pA sequence. The signal peptide of the mouse (aa.1-30) was retained.

Application

• Screening, development, and evaluation of IGF1R-targeted drugs.
• Study of the mechanisms and therapies for thyroid eye disease (TED).
• Study of the pathological mechanisms and treatments for growth retardation, diabetes, and cancer.

References
[1]Forbes BE, Blyth AJ, Wit JM. Disorders of IGFs and IGF-1R signaling pathways. Mol Cell Endocrinol. 2020 Dec 1;518:111035.
[2]Ma L, Zhao W, Huang S, Xu F, Wang Y, Deng D, Zhang T, Shu S, Chen X. IGF/IGF-1R signal pathway in pain: a promising therapeutic target. Int J Biol Sci. 2023 Jul 3;19(11):3472-3482.
[3]Wang P, Mak VC, Cheung LW. Drugging IGF-1R in cancer: New insights and emerging opportunities. Genes Dis. 2022 Mar 23;10(1):199-211.
[4]Walenkamp MJE, Robers JML, Wit JM, Zandwijken GRJ, van Duyvenvoorde HA, Oostdijk W, Hokken-Koelega ACS, Kant SG, Losekoot M. Phenotypic Features and Response to GH Treatment of Patients With a Molecular Defect of the IGF-1 Receptor. J Clin Endocrinol Metab. 2019 Aug;104(8):3157-3171.
[5]Neumann S, Krieger CC, Gershengorn MC. Targeting TSH and IGF-1 Receptors to Treat Thyroid Eye Disease. Eur Thyroid J. 2020 Dec;9(Suppl 1):59-65.
[6]Krieger CC, Sui X, Kahaly GJ, Neumann S, Gershengorn MC. Inhibition of TSH/IGF-1 Receptor Crosstalk by Teprotumumab as a Treatment Modality of Thyroid Eye Disease. J Clin Endocrinol Metab. 2022 Mar 24;107(4):e1653-e1660.