scholarly journals Dissecting the Effect of Genetic Variation on the Hepatic Expression of Drug Disposition Genes across the Collaborative Cross Mouse Strains

2016 ◽  
Vol 7 ◽  
Author(s):  
Aharon Nachshon ◽  
Hanifa J. Abu-Toamih Atamni ◽  
Yael Steuerman ◽  
Roa'a Sheikh-Hamed ◽  
Alexandra Dorman ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Drug Disposition ◽  
Collaborative Cross ◽  
Mouse Strains ◽  
Hepatic Expression ◽  
Disposition Genes

scholarly journals Time-Resolved Effect of Interferon-Alpha 2a on Activities of Nuclear Factor Kappa B, Pregnane X Receptor and on Drug Disposition Genes

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 808
Author(s):  
Dirk Theile ◽  
Lelia Wagner ◽  
Cindy Bay ◽  
Walter Emil Haefeli ◽  
Johanna Weiss
Keyword(s):  
Mrna Expression ◽  
Interferon Alpha ◽  
Nuclear Factor Kappa B ◽  
Drug Disposition ◽  
Pregnane X Receptor ◽  
Nuclear Factor ◽  
Cyp3a4 Activity ◽  
Time Resolved ◽  
Nuclear Factor Kappa ◽  
Disposition Genes

Interferon-alpha (IFN-α) is suggested to cause pharmacokinetic drug interactions by lowering expression of drug disposition genes through affecting the activities of nuclear factor kappa B (NF-ĸB) and pregnane X receptor (PXR). The time-resolved impact of IFN-α 2a (1000 U/mL; 5000 U/mL; 2 h to 30 h) on the activities of NF-ĸB and PXR and mRNA expression (5000 U/mL; 24 h, 48 h) of selected drug disposition genes and on cytochrome P450 (CYP3A4) activity in LS180 cells (5000 U/mL; 24 h, 48 h) was evaluated using luciferase-based reporter gene assays, reverse transcription polymerase chain reaction, and luminescence-based CYP3A4 activity assays. The cross-talk between NF-ĸB activation and PXR suppression was evaluated by NF-ĸB blockage (10 µM parthenolide). IFN-α 2a initially (2 h, 6 h) enhanced NF-ĸB activity 2-fold and suppressed PXR activity by 30%. mRNA of CYP3A4 was halved, whereas UGT1A1 was increased (1.35-fold) after 24 h. After 48 h, ABCB1 expression was increased (1.76-fold). CYP3A4 activity remained unchanged after 24 h, but was enhanced after 48 h (1.35-fold). IFN-α 2a demonstrated short-term suppressive effects on PXR activity and CYP3A4 mRNA expression, likely mediated by activated NF-ĸB. Longer exposure enhanced CYP3A4 activity. Clinical trials should evaluate the relevance by investigating the temporal effects of IFN-α on CYP3A4 using a sensitive marker substrate.

scholarly journals Common Heritable Immunological Variations Revealed in Genetically Diverse Inbred Mouse Strains of the Collaborative Cross

2018 ◽  
Vol 202 (3) ◽  
pp. 777-786 ◽  
Author(s):  
Roxanne Collin ◽  
Lois Balmer ◽  
Grant Morahan ◽  
Sylvie Lesage
Keyword(s):  
Inbred Mouse ◽  
Collaborative Cross ◽  
Mouse Strains ◽  
Inbred Mouse Strains

scholarly journals Genetic regulation of homeostatic immune architecture in the lungs of Collaborative Cross mice

2021 ◽  
Author(s):  
Brea K Hampton ◽  
Kara L. Jensen ◽  
Alan C. Whitmore ◽  
Colton L. Linnertz ◽  
Paul Maurizio ◽  
...  
Keyword(s):  
Immune Cell ◽  
Genetic Regulation ◽  
Reference Population ◽  
Collaborative Cross ◽  
System Stability ◽  
Mouse Strains ◽  
Cell Populations ◽  
Immune Homeostasis ◽  
Heritable Variation ◽  
Organ Systems

Variation in immune homeostasis, immune system stability, in organ systems such as the lungs is likely to shape the host response to infection at these exposed tissues. We evaluated immune homeostasis in immune cell populations in the lungs of the Collaborative Cross (CC) mouse genetic reference population. We found vast heritable variation in leukocyte populations with the frequency of many of these cell types showing distinct patterns relative to classic inbred strains C57BL/6J and BALB/cJ. We identified 28 quantitative trait loci (QTL) associated with variation in baseline lung immune cell populations, including several loci that broadly regulate the abundance of immune populations from distinct developmental lineages, and found that many of these loci have predictive value for influenza disease outcomes, demonstrating that genetic determinants of homeostatic immunity in the lungs regulate susceptibility to virus-induced disease. All told, we highlight the need to assess diverse mouse strains in understanding immune homeostasis and resulting immune responses.

scholarly journals Collaborative Cross Founder Expression Analysis (CCFEA)

2021 ◽  
Author(s):  
Richard R Green ◽  
Renee C Ireton ◽  
Martin Ferris ◽  
Kathleen Muenzen ◽  
David R Crosslin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Genetic Variation ◽  
Gene Expression Data ◽  
Viral Infections ◽  
Collaborative Cross ◽  
Visualization Tool ◽  
Expression Data ◽  
Individual Gene ◽  
Rnaseq Data

To understand the role of genetic variation in SARS and Influenza infections we developed CCFEA, a shiny visualization tool using public RNAseq data from the collaborative cross (CC) founder strains (A/J, C57BL/6J, 129s1/SvImJ, NOD/ShILtJ, NZO/HILtJ, CAST/EiJ, PWK/PhJ, and WSB/EiJ). Individual gene expression data is displayed across founders, viral infections and days post infection.

scholarly journals The dynamic effect of regulatory genetic variation on the in vivo ER stress transcriptional response

2021 ◽  
Author(s):  
Nikki D. Russell ◽  
Clement Y. Chow
Keyword(s):  
Genetic Variation ◽  
Stress Response ◽  
Er Stress ◽  
Transcriptional Response ◽  
Mouse Strains ◽  
Transcriptional Responses ◽  
Er Stress Response ◽  
Multiple Environments ◽  
Context Specific

AbstractGenotype x Environment (GxE) interactions occur when environmental conditions drastically change the effect of a genetic variant. In order to truly understand the effect of genetic variation, we need to incorporate multiple environments into our analyses. Many variants, under steady state conditions, may be silent or even have the opposite effect under stress conditions. This study uses an in vivo mouse model to investigate how the effect of genetic variation changes with tissue type and cellular stress. Endoplasmic reticulum (ER) stress occurs when misfolded proteins accumulate in the ER. This triggers the unfolded protein response (UPR), a large transcriptional response which attempts to return the cell to homeostasis. This transcriptional response, despite being a well conserved, basic cellular process, is highly variable across different genetic backgrounds, making it an ideal system to study GxE effects. In this study, we sought to better understand how genetic variation alters expression across tissues, in the presence and absence of ER stress. The use of different mouse strains and their F1s allow us to also identify context specific cis- and trans-regulatory mechanisms underlying variable transcriptional responses. We found hundreds of genes that respond to ER stress in a tissue- and/or genotype-dependent manner. Genotype-dependent ER stress-responsive genes are enriched for processes such as protein folding, apoptosis, and protein transport, indicating that some of the variability occurs in canonical ER stress factors. The majority of regulatory mechanisms underlying these variable transcriptional responses derive from cis-regulatory variation and are unique to a given tissue or ER stress state. This study demonstrates the need for incorporating multiple environments in future studies to better elucidate the effect of any particular genetic factor in basic biological pathways, like the ER stress response.Author SummaryThe effect of genetic variation is dependent on environmental context. Here we use genetically diverse mouse strains to understand how genetic variation interacts with stress state to produce variable transcriptional profiles. In this study, we take advantage of the endoplasmic reticulum (ER) stress response which is a large transcriptional response to misfolded proteins. Using this system, we uncovered tissue- and ER stress-specific effects of genetic variation on gene expression. Genes with genotype-dependent variable expression levels in response to ER stress were enriched for canonical ER stress functions, such as protein folding and transport. These variable effects of genetic variation are driven by unique sets of regulatory variation that are only active under context-specific circumstances. The results of this study highlight the importance of including multiple environments and genetic backgrounds when studying the ER stress response and other cellular pathways.

scholarly journals Genetic variation affects binge feeding behavior in female inbred mouse strains

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Brandon A. Newmyer ◽  
Ciarra M. Whindleton ◽  
Nandan Srinivasa ◽  
Marieke K. Jones ◽  
Michael M. Scott
Keyword(s):  
Genetic Variation ◽  
Food Intake ◽  
Feeding Behavior ◽  
Inbred Mouse ◽  
Treatment Strategies ◽  
Brain Regions ◽  
Mouse Strains ◽  
Inbred Mouse Strains ◽  
Behavioral Differences ◽  
Calorie Diet

Abstract Identifying genetic variants that regulate binge eating (BE) is critical for understanding the factors that control this behavior and for the development of pharmacological treatment strategies. Although several studies have revealed specific genes capable of affecting BE behavior, less is known about how genetic variation modulates BE. Thus, through a paradigm that promoted binge-like food intake through intermittent access to high calorie diet (HCD), we quantified food-intake in four inbred mouse strains: C57Bl/6J (B6), NOD/LtJ (NOD), 129S1/SvlmJ (S1), and A/J (AJ). We report that genetic variation likely influences the chronic regulation of food intake and the binge-like consumption of a palatable HCD. AJ mice consumed more of both standard chow and HCD than the other three strains tested when both diets were available ad libitum, while S1 mice consumed significantly less HCD than other strains during intermittent HCD access. Behavioral differences were also associated with differential changes in c-Fos immunohistochemistry in brain regions traditionally associated with appetite regulation. Our results identify 129S1/SvlmJ as a strain that exhibits low levels of binge feeding behavior and suggests that this strain could be useful in the investigation of the influence of genetic variation in the control of binge food intake.

scholarly journals Publisher Correction: Genetic variation affects binge feeding behavior in female inbred mouse strains

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Brandon A. Newmyer ◽  
Ciarra M. Whindleton ◽  
Nandan Srinivasa ◽  
Marieke K. Jones ◽  
Michael M. Scott
Keyword(s):  
Genetic Variation ◽  
Feeding Behavior ◽  
Inbred Mouse ◽  
Mouse Strains ◽  
Inbred Mouse Strains
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