Congenic mice demonstrate the presence of QTLs conferring obesity and hypercholesterolemia on chromosome 1 in the TALLYHO mouse

Parkman, Jacaline; Denvir, James; Mao, Xia; Dillon, Kristy; Romero, Sofia; Saxton, Arnold M.; Kim, Jung Han

doi:10.1007/s00335-017-9719-2

Cited by 10 publications

(3 citation statements)

References 39 publications

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“…Our strategy for reducing the Blmpf1 genetic interval was to phenotype a panel of subcongenic mice and to evaluate the DNA variation within the identified set of positional candidate genes as has been used by others (Maegawa et al 2018 ; Parkman et al 2017 ). In detail, Parkman et al ( 2017 ) studied lines of congenic mice to verify a locus of obesity and hypercholesterolemia, previously identified with linkage data, and interrogated the resultant gene list for variation with the potential to alter the protein sequence. Similarly, Maegawa et al ( 2018 ) used DNA sequence comparisons to support a candidate gene for diabetes susceptibility in a genomic region identified through testing a panel of congenic mice.…”

Section: Discussionmentioning

confidence: 99%

Fine mapping of the major bleomycin-induced pulmonary fibrosis susceptibility locus in mice

2018

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Susceptibility to fibrotic lung disease differs among people and among inbred strains of mice exposed to bleomycin where C57BL/6J mice are susceptible and C3H/HeJ mice are spared fibrotic disease. Genetic mapping studies completed in offspring derived from these inbred strains revealed the inheritance of C57BL/6J alleles at loci, including the major locus on chromosome 17, called Blmpf1 bleomycin-induced pulmonary fibrosis 1, to be linked to pulmonary fibrosis in treated mice. In the present study, to reduce the interval of Blmpf1, we bred and phenotyped a panel of subcongenic mice with C3H/HeJ alleles in a C57BL/6J background. Subcongenic mice received bleomycin via osmotic minipump and the fibrosis phenotype was measured histologically. Inheritance of C3H/HeJ alleles from 34.31 to 35.02 Mb was revealed to spare bleomycin-induced pulmonary fibrosis of C57BL/6J mice. From database analysis, 40 protein coding genes have been mapped to this reduced Blmpf1 interval, 18 of which contain C57BL/6J:C3H/HeJ sequence polymorphisms predicted to affect protein structure or to confer allele-dependent expression, and by RT-PCR analysis of lung tissue, we show 6 of these genes to differ in expression between C57BL/6J and C3H/HeJ mice. Genes known to regulate T cell numbers and activation (Btnl family, Notch4) are among the limited list of potential causal variants leading to lung disease in this model and the bronchoalveolar lavage of protected subcongenic mice had fewer lymphocytes, post bleomycin, than did C57BL/6J mice. We conclude that Blmpf1genes contributing to the susceptibility to bleomycin-induced pulmonary fibrosis could alter the adaptive immune response of C57BL/6J mice.Electronic supplementary materialThe online version of this article (10.1007/s00335-018-9774-3) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Fine mapping of the major bleomycin-induced pulmonary fibrosis susceptibility locus in mice

2018

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“…High blood glucose and hypertension are the leading cause of CKD. Given the occurrence of single gene mutations causing obesity in humans is rare, the polygenic obese TH mice appear to be an accurate replica of either human genetics or physiology [30,31,32], representing a suitable animal model to investigate the potential diagnostic and therapeutic approach for human obesity and metabolic syndrome-related kidney diseases.…”

Section: Discussionmentioning

confidence: 99%

Metabolic Syndrome and Salt-Sensitive Hypertension in Polygenic Obese TALLYHO/JngJ Mice: Role of Na/K-ATPase Signaling

Yan

Wang

Chaudhry

et al. 2019

IJMS

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We have demonstrated that Na/K-ATPase acts as a receptor for reactive oxygen species (ROS), regulating renal Na+ handling and blood pressure. TALLYHO/JngJ (TH) mice are believed to mimic the state of obesity in humans with a polygenic background of type 2 diabetes. This present work is to investigate the role of Na/K-ATPase signaling in TH mice, focusing on susceptibility to hypertension due to chronic excess salt ingestion. Age-matched male TH and the control C57BL/6J (B6) mice were fed either normal diet or high salt diet (HS: 2, 4, and 8% NaCl) to construct the renal function curve. Na/K-ATPase signaling including c-Src and ERK1/2 phosphorylation, as well as protein carbonylation (a commonly used marker for enhanced ROS production), were assessed in the kidney cortex tissues by Western blot. Urinary and plasma Na+ levels were measured by flame photometry. When compared to B6 mice, TH mice developed salt-sensitive hypertension and responded to a high salt diet with a significant rise in systolic blood pressure indicative of a blunted pressure-natriuresis relationship. These findings were evidenced by a decrease in total and fractional Na+ excretion and a right-shifted renal function curve with a reduced slope. This salt-sensitive hypertension correlated with changes in the Na/K-ATPase signaling. Specifically, Na/K-ATPase signaling was not able to be stimulated by HS due to the activated baseline protein carbonylation, phosphorylation of c-Src and ERK1/2. These findings support the emerging view that Na/K-ATPase signaling contributes to metabolic disease and suggest that malfunction of the Na/K-ATPase signaling may promote the development of salt-sensitive hypertension in obesity. The increased basal level of renal Na/K-ATPase-dependent redox signaling may be responsible for the development of salt-sensitive hypertension in polygenic obese TH mice.

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“…Compared to the laboratory lines, the wild mice have more abundant genetic polymorphisms and could serve as better donor mice [24,25]. Chromosome 1 (Chr 1) contains multiple gene loci related to blood lipid metabolism [26][27][28][29][30]. Professor Xiao's group constructed new lines named Chr 1 substitution lines with wild mice from different areas of China [31][32][33][34][35].…”

Section: Introductionmentioning

confidence: 99%

Identification of a Chromosome 1 Substitution Line B6-Chr1BLD as a Novel Hyperlipidemia Model via Phenotyping Screening

Sun

Qi³

et al. 2022

Metabolites

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Hyperlipidemia is a chronic disease that seriously affects human health. Due to the fact that traditional animal models cannot fully mimic hyperlipidemia in humans, new animal models are urgently needed for basic drug research on hyperlipidemia. Previous studies have demonstrated that the genomic diversity of the wild mice chromosome 1 substitution lines was significantly different from that of laboratory mice, suggesting that it might be accompanied by phenotypic diversity. We first screened the blood lipid-related phenotype of chromosome 1 substitution lines. We found that the male HFD-fed B6-Chr1BLD mice showed more severe hyperlipidemia-related phenotypes in body weight, lipid metabolism and liver lesions. By RNA sequencing and whole-genome sequencing results of B6-Chr1BLD, we found that several differentially expressed single nucleotide polymorphism enriched genes were associated with lipid metabolism-related pathways. Lipid metabolism-related genes, mainly including Aida, Soat1, Scly and Ildr2, might play an initial and upstream role in the abnormal metabolic phenotype of male B6-Chr1BLD mice. Taken together, male B6-Chr1BLD mice could serve as a novel, polygenic interaction-based hyperlipidemia model. This study could provide a novel animal model for accurate clinical diagnosis and precise medicine of hyperlipidemia.

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Congenic mice demonstrate the presence of QTLs conferring obesity and hypercholesterolemia on chromosome 1 in the TALLYHO mouse

Cited by 10 publications

References 39 publications

Fine mapping of the major bleomycin-induced pulmonary fibrosis susceptibility locus in mice

Fine mapping of the major bleomycin-induced pulmonary fibrosis susceptibility locus in mice

Metabolic Syndrome and Salt-Sensitive Hypertension in Polygenic Obese TALLYHO/JngJ Mice: Role of Na/K-ATPase Signaling

Identification of a Chromosome 1 Substitution Line B6-Chr1BLD as a Novel Hyperlipidemia Model via Phenotyping Screening

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