Genetic mapping in Diversity Outbred mice identifies a Trpa1 variant influencing late-phase formalin response

ABSTRACTIdentification of genetic variants that influence susceptibility to chronic pain is key to identifying molecular mechanisms and targets for effective and safe therapeutic alternatives to opioids. To identify genes and variants associated with chronic pain, we measured late phase response to formalin injection in 275 male and female Diversity Outbred (DO) mice genotyped for over 70 thousand SNPs. One quantitative trait locus (QTL) reached genome-wide significance on chromosome 1 with a support interval of 3.1 Mb. This locus,Nociq4(nociceptive sensitivity inflammatory QTL 4; MGI:5661503), harbors the well-known pain geneTrpa1(transient receptor potential cation channel, subfamily A, member 1).Trpa1is a cation channel known to play an important role in acute and chronic pain in both humans and mice. Analysis of DO founder strain allele effects revealed a significant effect of the CAST/EiJ allele atTrpa1, with CAST/EiJ carrier mice showing an early, but not late, response to formalin relative to carriers of the seven other inbred founder alleles (A/J, C57BL/6J, 129S1/SvImJ, NOD/ShiLtJ, NZO/HlLtJ, PWK/PhJ, and WSB/EiJ). We characterized possible functional consequences of sequence variants inTrpa1by assessing channel conductance,Trpa1/Trpv1interactions, and isoform expression. The phenotypic differences observed in CAST/EiJ relative to C57BL/6J carriers were best explained byTrpa1isoform expression differences, implicating a splice junction variant as the causal functional variant. This study demonstrates the utility of advanced, high-precision genetic mapping populations in resolving specific molecular mechanisms of variation in pain sensitivity.

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Quantitative trait mapping in Diversity Outbred mice identifies novel genomic regions associated with the hepatic glutathione redox system

Redox Biology ◽

10.1016/j.redox.2021.102093 ◽

2021 ◽

pp. 102093

Author(s):

Rebecca L. Gould ◽

Steven W. Craig ◽

Susan McClatchy ◽

Gary A. Churchill ◽

Robert Pazdro

Keyword(s):

Quantitative Trait ◽

Redox System ◽

Glutathione Redox System ◽

Trait Mapping ◽

Quantitative Trait Mapping ◽

Diversity Outbred ◽

Hepatic Glutathione ◽

Outbred Mice ◽

Genomic Regions ◽

Glutathione Redox

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Abstract P060: Identification of host-intrinsic resistance mechanisms to immune checkpoint inhibitors (ICI) in Diversity Outbred mice

10.1158/2326-6074.tumimm21-p060 ◽

2022 ◽

Author(s):

Justin Hackett ◽

James Glassbrook ◽

Maria Muniz ◽

Heather M. Gibson

Keyword(s):

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Resistance Mechanisms ◽

Intrinsic Resistance ◽

Diversity Outbred ◽

Outbred Mice

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Correction to: Quantitative trait mapping in Diversity Outbred mice identifies two genomic regions associated with heart size

Mammalian Genome ◽

10.1007/s00335-018-9789-9 ◽

2018 ◽

Vol 30 (1-2) ◽

pp. 42-42

Author(s):

John R. Shorter ◽

Wei Huang ◽

Ju Youn Beak ◽

Kunjie Hua ◽

Daniel M. Gatti ◽

...

Keyword(s):

Quantitative Trait ◽

Trait Mapping ◽

Quantitative Trait Mapping ◽

Diversity Outbred ◽

Heart Size ◽

Outbred Mice ◽

Genomic Regions

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Comparison of the Susceptibilities of C57BL/6 and A/J Mouse Strains to Streptococcus suis Serotype 2 Infection

Infection and Immunity ◽

10.1128/iai.00350-08 ◽

2008 ◽

Vol 76 (9) ◽

pp. 3901-3910 ◽

Cited By ~ 50

Author(s):

María de la Cruz Domínguez-Punaro ◽

Mariela Segura ◽

Danuta Radzioch ◽

Serge Rivest ◽

Marcelo Gottschalk

Keyword(s):

Septic Shock ◽

Inbred Mice ◽

Late Phase ◽

Streptococcus Suis ◽

Mouse Strains ◽

Necrosis Factor Alpha ◽

Central Nervous System Damage ◽

Proinflammatory Mediators ◽

Outbred Mice

ABSTRACT Streptococcus suis is an important swine and human pathogen. Assessment of susceptibility to S. suis using animal models has been limited to monitoring mortality rates. We recently developed a hematogenous model of S. suis infection in adult CD1 outbred mice to study the in vivo development of an early septic shock-like syndrome that leads to death and a late phase that clearly induces central nervous system damage, including meningitis. In the present study, we compared the severities of septic shock-like syndrome caused by S. suis between adult C57BL/6J (B6) and A/J inbred mice. Clinical parameters, proinflammatory mediators, and bacterial clearance were measured to dissect potential immune factors associated with genetic susceptibility to S. suis infection. Results showed that A/J mice were significantly more susceptible than B6 mice to S. suis infection, especially during the acute septic phase of infection (100% of A/J and 16% of B6 mice died before 24 h postinfection). The greater susceptibility of A/J mice was associated with an exaggerated inflammatory response, as indicated by their higher production of tumor necrosis factor alpha, interleukin-12p40/p70 (IL-12p40/p70), gamma interferon, and IL-1β, but not with different bacterial loads in the blood. In addition, IL-10 was shown to be responsible, at least in part, for the higher survival in B6 mice. Our findings demonstrate that A/J mice are very susceptible to S. suis infection and provide evidence that the balance between pro- and anti-inflammatory mediators is crucial for host survival during the septic phase.

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