We replaced the gene for the low density lipoprotein receptor (LDLR) in mice with the human equivalent. LDLR is important for cholesterol clearance from circulation and an elevated plasma cholesterol level is the major risk factor for atherosclerosis and coronary heart disease. These mice can be used to investigate gene-gene and gene-environment interactions that present in human lipid metabolism and heart disease. It can also be used to test therapeutic molecules that interact with human LDLR-mediated lipid clearance. These mice are available at The Jackson Laboratory and can be found at https://www.jax.org/strain/012307. 

Mutations in cryopyrin (NLRP3), a large protein functioning as an important immune pathway in human disease, have been identified in most patients with autoinflammatory disorders. The severity of the disease is likely related to the degree a particular mutation alters the protein. This mouse line, in which the NLRP3 locus has been excised and replaced with its human counterpart, shows value as a platform to test therapeutic reagents targeting the human inflammasome. Human NLRP3 proteins function in vivo and demonstrate the human inflammasome’s ability to trigger immune reactions to innate stimuli. Closely related to UNC Ref# 14-0063 (Mouse: NLRP3 Null). If you are an academic institution or nonprofit organization interested in this research tool for noncommercial purposes, please contact the researcher directly to inquire about availability.

Abstract Pitt-Hopkins syndrome (PTHS) is a severe neurodevelopmental disorder, characterized by delay in motor function, lack of speech, stereotypies, sleep disorder, seizures, and intellectual disability. THS is caused by monoallelic mutation or deletion of transcription factor 4 (TCF4), which is a member of the class I basic-helix-loop-helix (bHLH) group. Here, Researchers designed a humanized trangenic mouse model to establish the extent to which conditional reinstatement of Tcf4 expression could rescue behavioral phenotypes in a mouse model of PTHS. Researchers at UNC have developed a humanized transgenic knock-in Tcf4-P2A-H2B-EGFP-T2A-Nanoluciferase (hTcf4-EGFP-Nluc) reporter mouse in which 8.5 kb of transcriptional start site region and 6 kb region downstream of the stop codon of mouse Tcf4 have been replaced by corresponding human sequences. a reporter cassette P2A-H2B-EGFP-T2A-Nluc was inserted immediately upstream from Tcf4 stop codon in which reporters H2A-EGFP (EGFP protein fused to human histone H2B protein) and Nanoluciferase (Nluc) are cleaved from translated Tcf4 protein by two self-cleaving peptides P2A and T2A. To select for the transgene insertions in embryonic stem cells, a neomycin and hygromycin cassettes flanked by F3 (mutant FRT) sites were inserted upstream and downstream of the human TCF4 sequences, respectively. Pan-cellular embryonic reinstatement of Tcf4 fully rescues behavioral phenotypes in a PTHS mouse model. If you are an academic institution or nonprofit organization interested in this research tool for noncommercial purposes, please contact the researcher directly to inquire about availability. Categories Research Tools         Mouse Lines Therapeutics by Clinical Indication        Neurology

Hunter syndrome is a lysosomal storage disease that is caused by deficiency or absence of iduronate-2-sulfatase (I2S). This mouse model for Hunter Syndrome was created by disrupting the mouse I2S gene. The iduronate sulfatase deficient mice provide a tool for the study of the pathophysiology of Hunter Syndrome and for the development of new therapies for lysosomal storage disorders, such as enzyme replacement and gene therapy.     If you are an academic institution or nonprofit organization interested in this research tool for noncommercial purposes, please contact the researcher directly to inquire about availability.

Gene-targeted B6129SF2/J mice in which the cytoplasmic kinase domain was replaced with the neomycin-resistant gene. The specific mutation in mer permits functional analyses in signal transduction while avoiding developmental anomalies that may arise from complete ablation of the gene. Mer mice are extremely sensitive to endotoxin (LPS) treatment. These mice exhibit excessive TNF-a production and increased susceptibility to lethal septic shock. If you are an academic institution or nonprofit organization interested in this research tool for noncommercial purposes, please contact the researcher directly to inquire about availability.

Abstract These mice possess loxP sites on either side of the Mgp gene, which allows for the creation of trabecular meshwork and peripapillary sclera conditional knockouts. Unlike mice containing global knockout of Mgp, when these mice are bred to mice that express Cre recombinase, the resulting offspring will have exon 2 and exon 3 deleted in only the cre-expressing tissues, which can provide better insight to the function of Mgp in eye stiffness. A primary role of Mgp is inhibition of calcification, and consequently these mice are invaluable for the creation of stiffness mouse models in glaucoma. If you are an academic institution or nonprofit organization interested in this research tool for noncommercial purposes, this mouse line is available at Jackson Laboratories (Stock # 037521) https://www.jax.org/strain/037521 Category: Research Tools: Mouse Line

GPAT initiates the synthesis of triacylglycerol and phospholipids, which play a critical role in disorders such as obesity, diabetes, and atherosclerosis. GPAT knockout mice are slim, resistant to fatty liver, appear to be resistant to diet-induced obesity, and are insulin-sensitive. Additionally, this mouse model has an abnormal phospholipid fatty acid composition that may cause them to respond differently to inflammatory stimuli. If you are an academic institution or nonprofit organization interested in this research tool for noncommercial purposes, this mouse is available from Jackson Laboratories (Stock No 005429). https://www.jax.org/strain/005429

Prostaglandins are lipid mediators produced by all cell types and regulate multiple biological processes. Prostaglandin E2 (PGE2) has been specifically implicated in many pathological conditions such as inflammation and epithelial cancers. This mouse line is homozygous for the null allele of mPGES-2, one of three enzymes capable of PGE2 synthesis in vitro. This line has no detectable levels of mPGES-2, however has wild-type levels of PGE2 in many tissues examined. These mice are available from The Jackson Laboratory and can be found at https://www.jax.org/strain/009135. 

Nlrp1b encodes a pattern recognition receptor that is involved in the formation of the inflammasome, which regulates the immune system's response to injury, toxins, and infection by cleaving interleukin (IL)-1β. Nlrp1b is specifically activated upon sensing the anthrax lethal toxin and the resulting release of pro-inflammatory cytokines aids in the clearance of the anthrax infection. Homozygous Nlrp3-deficient mice are viable and fertile. Bone marrow derived macrophages from these Nlrp1b-/- mice are not sensitive to anthrax LT challenge. These mice are able to form the inflammasome and activate caspase-1. Caspase-1 activation in these mice leads to pyroptosis, which results in acute lung injury and morbidity within 3 days of infection. If you are an academic institution or nonprofit organization interested in this research tool for noncommercial purposes, please contact the researcher directly to inquire about availability.

Acute inflammation in response to both exogenous and endogenous danger signals can lead to the assembly of cytoplasmic inflammasomes that stimulate the activation of caspase-1, which facilitates the maturation and release of cytokines and sometimes the induction of cell death by pyroptosis. This mouse line, which allows for study of the role of the inflammasome in the immune response, was generated by targeted mutagenesis in 129 ES cells using a replacement type vector. This removed all NLRP3 exons and replaced the segment of DNA with the neomycin resistance gene. Closely related to UNC Ref# 17-0083 (Mouse: Humanized NLRP3). This research tool is available from The Jackson Laboratory at https://www.jax.org/strain/021302.