B6-hPD-1/hVEGFA Mice

Catalog Number: C001598

Strain Name: C57BL/6JCya-Pdcd1em1(hPDCD1)Vegfatm1(hVEGFA)/Cya

Genetic Background: C57BL/6JCya

Reproduction: Homozygote x Homozygote

 

Strain Description

Programmed cell death protein 1 (PDCD1/PD-1) is a member of the B7-CD28 costimulatory receptor family. It is an inhibitory receptor expressed on activated T cells and plays a role in regulating the function of effector T cells, including CD8+ T cells, and promoting the differentiation of CD4+ T cells into regulatory T cells. PD-1 is expressed in a variety of tumors and plays an important role in antitumor immunity. In addition, PD-1 is involved in the defense against autoimmune diseases and has inhibitory effects on antitumor and antimicrobial immunity [1]. PD-1 binds to programmed death ligands 1 and 2 (PD-L1 and PD-L2) to inhibit T cell activation, reduce the production of corresponding cytokines, and regulate T cell survival [2]. Drugs targeting this pathway can reactivate T cells to activate antitumor immune responses [3].

The Vascular Endothelial Growth Factor (VEGF) family is a group of particular endothelial growth factors intimately associated with angiogenesis. These factors promote increased vascular permeability, extracellular matrix degeneration, vascular endothelial cell migration and proliferation, and are capable of stimulating angiogenesis and increasing the permeability of existing vessels. As such, they play a pivotal role in normal vascular development and wound healing. The VEGF family comprises VEGFA, VEGFB, VEGFC, VEGFD, VEGFE, and PLGF [4]. Of these, VEGFA is the most commonly targeted in research related to neovascular ophthalmic diseases due to its crucial role in the proliferation, migration, and formation of endothelial cell microvessels [5]. Overexpression of VEGFA in the eye can result in abnormal vascular growth and leakage, leading to various ophthalmic diseases such as Age-Related Macular Degeneration (AMD), Diabetic Retinopathy (DR), and corneal neovascularization [5-6]. The progression of solid tumors depends on vascularization and angiogenesis within malignant tissues, with VEGFA playing a crucial role among various pro-angiogenic factors. The VEGFA gene is upregulated in many known tumors, correlating with tumor staging and progression. Blocking VEGFA may lead to vascular network regression, inhibiting tumor growth [7]. Thus, VEGFA is an important target for anti-angiogenic cancer therapies.

The B6-hPD-1/hVEGFA mouse is a humanized model obtained by crossbreeding hPD-1 mice (Catalog No. C001524) with B6-hVEGFA mice (Catalog No. C001555). This model can be used for research in drug development, efficacy and safety evaluation, tumor immunotherapy evaluation, and immune system mechanisms related to human PD-1/VEGFA.

Strain Strategy

  • Construction strategy for hPD-1 mice: The mouse Pdcd1 gene was edited using gene editing technology to replace the sequence encoding the extracellular domain of mouse PD-1 protein (aa.25~169) with the sequence from the human PD1 gene encoding the human PD-1 protein extracellular domain (aa.24~170) while retaining the mouse signal peptide.



  • Construction strategy for B6-hVEGFA mice: The sequence from the CTG start codon to 3'UTR of the mouse Vegfa gene was replaced with the sequence from the CTG start codon to 3'UTR of the human VEGFA gene.



Applications

  • Drug screening, efficacy evaluation, and safety assessment related to human PD-1/VEGFA;
  • Tumor immunotherapy and mechanisms of the immune system.

 

References
[1]National Center for Biotechnology Information. "Gene: PDCD1." NCBI, U.S. National Library of Medicine, 2023, www.ncbi.nlm.nih.gov/gene/5133
[2]Okazaki T, Honjo T. PD-1 and PD-1 ligands: from discovery to clinical application. Int Immunol. 2007 Jul;19(7):813-24.
[3]Sharpe AH, Pauken KE. The diverse functions of the PD1 inhibitory pathway. Nat Rev Immunol. 2018 Mar;18(3):153-167.
[4]Hoeben A, Landuyt B, Highley MS, Wildiers H, Van Oosterom AT, De Bruijn EA. Vascular endothelial growth factor and angiogenesis. Pharmacol Rev. 2004 Dec;56(4):549-80.
[5]Apte RS, Chen DS, Ferrara N. VEGF in Signaling and Disease: Beyond Discovery and Development. Cell. 2019 Mar 7;176(6):1248-1264.
[6]Mesquita J, Castro-de-Sousa JP, Vaz-Pereira S, Neves A, Passarinha LA, Tomaz CT. Vascular endothelial growth factors and placenta growth factor in retinal vasculopathies: Current research and future perspectives. Cytokine Growth Factor Rev. 2018 Feb;39:102-115.
[7]Chekhonin VP, Shein SA, Korchagina AA, Gurina OI. VEGF in tumor progression and targeted therapy. Curr Cancer Drug Targets. 2013 May;13(4):423-43.