Project description:Deletion of the glycerol channel aquaporin-9 (Aqp9) reduces postprandial blood glucose levels in leptin receptor deficient (db/db) obese mice on a C57BL/6×C57BLKS mixed genetic background. Furthermore, shRNA mediated reduction of Aqp9 expression reduces liver triacylglycerol (TAG) accumulation in a diet induced rat model of obesity. The aim of this study was to investigate metabolic effects of Aqp9 deletion in coisogenic db/db mice of the C57BL/6 background. Aqp9wt db/db and Aqp9-/- db/db mice did not differ in body weight and liver TAG contents. On the C57BL/6 genetic background we observed elevated plasma glucose in Aqp9-/- db/db mice (+ 1.1 mM, life-time average) while plasma insulin concentration was reduced at time of death. Glucose levels changed similarly in pentobarbital anesthetized, glucagon challenged Aqp9wt db/db and Aqp9-/- db/db mice. Liver transcriptional profiling did not detect differential gene expression between genotypes. Metabolite profiling revealed a sex independent increase in plasma glycerol (+55%), glucose (+24%) and reduction in threonate (all at q<0.1) in Aqp9-/- db/db mice compared to controls. Metabolite profiling thus confirms a role of AQP9 in glycerol metabolism of obese C57BL/6 db/db mice. In this animal model of obesity Aqp9 gene deletion elevates plasma glucose and does not alleviate hepatosteatosis.
Project description:The RNA-binding protein FUS is implicated in transcription, alternative splicing of neuronal genes and DNA repair. Mutations in FUS have been linked to human neurodegenerative diseases such as ALS (amyotrophic lateral sclerosis). We genetically disrupted fus in zebrafish (Danio rerio) using the CRISPR-Cas9 system. The fus knockout animals are fertile and did not show any distinctive phenotype. Mutation of fus induces mild changes in gene expression on the transcriptome and proteome level in the adult brain. We observed a significant influence of genetic background on gene expression and 3’UTR usage, which could mask the effects of loss of Fus. Unlike published fus morphants, maternal zygotic fus mutants do not show motoneuronal degeneration and exhibit normal locomotor activity.
Project description:Traumatic brain injury (TBI) pathologies are caused by primary and secondary injuries. Primary injuries result from physical damage to the brain, and secondary injuries arise from cellular responses to primary injuries. A characteristic cellular response is sustained activation of inflammatory pathways commonly mediated by NF-B transcription factors. Using a Drosophila melanogaster TBI model, we previously found that the main proximal transcriptional response to primary injuries is triggered by activation of Toll and Imd innate immune response pathways that engage NF-B factors Dif and Relish (Rel), respectively. Here, we monitor the abundance of Rel protein by mass spectrometry (MS) and observe that Rel increases in fly heads at 4-8 h after TBI. To investigate the necessity of Rel for secondary injuries, we generated a null allele, Reldel, by CRISPR/Cas9 editing. Heterozygous but not homozygous Reldel mutation reduced mortality at 24 h after TBI and increased the lifespan of injured flies. Additionally, the effect of heterozygous Reldel mutation on mortality was modulated by genetic background and diet. To identify genes that facilitate effects of heterozygous Reldel mutation on TBI outcomes, we compared genome-wide mRNA expression profiles of uninjured and injured +/+, +/Reldel, and Reldel/Reldel flies at 4 h following TBI. Only a few genes changed expression more than two-fold in +/Reldel flies relative to +/+ and Reldel/Reldel flies, and they were not canonical innate immune response genes. Therefore, Rel is necessary for TBI-induced secondary injuries but in complex ways involving Rel gene dose, genetic background, diet, and possibly small changes in expression of innate immune response genes.
Project description:AIMS To identify the underlying mechanism by which Vitamin D reduces colorectal cancer risk.
OBJECTIVES To demonstrate the effects of vitamin D supplementation on serum vitamin D levels.
To demonstrate dynamic changes in gene expression in response to vitamin D. To demonstrate the mechanism underlying the gene-environment interaction of vitamin D, susceptibility genetic variants (risk genes) and colorectal cancer.
Project description:Assessed steady-state transcription in whole brain and two more specific brain regions. Studied the impact of strain genetic background on expression levels. In addition, we also studied the effects of acute clozapine exposure on gene expression in mouse brain.
Project description:The purpose of this interventional study is to investigate whether there is evidence that panitumumab in combination with XELOX (capecitabine plus oxaliplatin) chemotherapy will safely increase progression-free survival, above that of XELOX alone in subjects with KRAS wild-type metastatic colorectal cancer who have not responded to or progressed after first line therapy with irinotecan and a fluoropyrimidine.
Further Objectives Exploratory objectives may include investigation of potential correlations between the treatment regimen and epidermal growth factor receptor (EGFR) expression, detection of the functional genetic polymorphisms of the EGFR gene, EGFR gene amplification (FISH), EGFR downstream protein and gene expression parameters, proteomics and epigenetics.
Project description:Examination of gene expression changes during hypoxia of the Fawn Hooded Hypertensive (FHH) rat and FHH12BN consomic rat. FHH12BN rats are derived from introgression chromosome 12 from Brown Norway (BN) rat into the FHH genetic background
Project description:Examination of gene expression changes during hypoxia of the Dahl salt sensative (SS) rat and SS4BN consomic rat. SS4BN rats are derived from introgression of chromosome 4 from Brown Norway (BN) rat into the genetic background.
Project description:Examination of gene expression changes during hypoxia of the Dahl salt sensative (SS) rat and SS11BN consomic rat. SS11BN rats are derived from introgression of chromosome 11 from Brown Norway (BN) rat into the SS genetic background.
Project description:Examination of gene expression changes during hypoxia of the Dahl salt sensitive (SS) rat and SS13BN consomic rat. SS13BN rats are derived from introgression of chromosome 13 from Brown Norway (BN) rat into the SS genetic background.