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RNAseq data on single dose KMO inhibitor (CHDI-00340246) treated R6/2 mice.

ABSTRACT: Dysregulation of the kynurenine (Kyn) pathway has been associated with the progression of Huntington's disease (HD). In particular, elevated levels of the kynurenine metabolites 3-hydroxy kynurenine (3-OH-Kyn) and quinolinic acid (Quin), have been reported in the brains of HD patients as well as in rodent models of HD. The production of these metabolites is controlled by the activity of kynurenine mono-oxygenase (KMO), a mitochondrial outer membrane enzyme which catalyzes the synthesis of 3-OH-Kyn from Kyn. Thus inhibiting KMO is expected to produce a beneficial effect in Huntington's Disease (HD) patients, hopefully reversing their phenotype to match healthy subjects. To test this effect, we acutely treated a mouse model of HD (R6/2, a transgenic mouse model of HD which contains a human HTT gene containing 90 CAG repeats) and wild type mice with a KMO inhibitor, and separately used a mock treatment on both the transgenic mice and wild type mice. The goal of this project is to analyze the RNA-seq data and find gene expression changes associated with the KMO inhibitor

ORGANISM(S): Mus musculus

PROVIDER: GSE106161 | GEO | 2017/10/30

SECONDARY ACCESSION(S): PRJNA415795

REPOSITORIES: GEO

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RNA-Seq data on KMO inhibitor (CHDI-00340246) subchronic treated R6/2 mice.

Project description:Dysregulation of the kynurenine (Kyn) pathway has been associated with the progression of Huntington's disease (HD). In particular, elevated levels of the kynurenine metabolites 3-hydroxy kynurenine (3-OH-Kyn) and quinolinic acid (Quin), have been reported in the brains of HD patients as well as in rodent models of HD. The production of these metabolites is controlled by the activity of kynurenine mono-oxygenase (KMO), a mitochondrial outer membrane enzyme which catalyzes the synthesis of 3-OH-Kyn from Kyn. Thus inhibiting KMO is expected to produce a beneficial effect in Huntington's Disease (HD) patients, hopefully reversing their phenotype to match healthy subjects. To test this effect, we chronically treated a mouse model of HD (R6/2, a transgenic mouse model of HD which contains a human HTT gene containing 90 CAG repeats) and wild type mice with a KMO inhibitor for 8 weeks, and separately used a mock treatment on both the transgenic mice and wild type mice. The goal of this project is to analyze the RNA-seq data and find gene expression changes associated with the KMO inhibitor.

2017-10-30 | GSE105158 | GEO

Plasma kynurenine mediated pathological communication between gut microbiota and ventricular remodeling in children with pressure overload

Project description:Abnormally elevated plasma kynurenine (Kyn) was detected in the patient cohort and single nuclues sequecing revealed its molecular role

2023-07-19 | GSE210833 | GEO

Transcription profiling of striatum from 12 weeks-old R6/2 mice and control mice (set 2)

Project description:To test the hypotheses that mutant huntingtin protein length and wild-type huntingtin dosage have important effects on disease-related transcriptional dysfunction, we compared the changes in mRNA in seven genetic mouse models of Huntington's disease (HD) and postmortem human HD caudate. Transgenic models expressing short N-terminal fragments of mutant huntingtin (R6/1 and R6/2 mice) exhibited the most rapid effects on gene expression, consistent with previous studies. Although changes in the brains of knock-in and full-length transgenic models of HD took longer to appear, 15- and 22-month CHL2(Q150/Q150), 18-month Hdh(Q92/Q92) and 2-year-old YAC128 animals also exhibited significant HD-like mRNA signatures. Whereas it was expected that the expression of full-length huntingtin transprotein might result in unique gene expression changes compared with those caused by the expression of an N-terminal huntingtin fragment, no discernable differences between full-length and fragment models were detected. In addition, very high correlations between the signatures of mice expressing normal levels of wild-type huntingtin and mice in which the wild-type protein is absent suggest a limited effect of the wild-type protein to change basal gene expression or to influence the qualitative disease-related effect of mutant huntingtin. The combined analysis of mouse and human HD transcriptomes provides important temporal and mechanistic insights into the process by which mutant huntingtin kills striatal neurons. In addition, the discovery that several available lines of HD mice faithfully recapitulate the gene expression signature of the human disorder provides a novel aspect of validation with respect to their use in preclinical therapeutic trials. Experiment Overall Design: Striatal samples from 5 R6/2 mutant mice (12 weeks-old) and 4 age-matched wild-type mice.

2008-06-16 | E-GEOD-9804 | biostudies-arrayexpress

Striatal gene expression data from 12 weeks-old R6/2 mice and control mice (set 2)

2007-12-17 | GSE9804 | GEO

Striatal gene expression data from 12 weeks-old R6/2 mice and control mice (set 1)

2007-12-17 | GSE9803 | GEO

Transcription profiling of mouse striatum from 12 weeks-old R6/2 mice and control mice (set 1)

Project description:To test the hypotheses that mutant huntingtin protein length and wild-type huntingtin dosage have important effects on disease-related transcriptional dysfunction, we compared the changes in mRNA in seven genetic mouse models of Huntington's disease (HD) and postmortem human HD caudate. Transgenic models expressing short N-terminal fragments of mutant huntingtin (R6/1 and R6/2 mice) exhibited the most rapid effects on gene expression, consistent with previous studies. Although changes in the brains of knock-in and full-length transgenic models of HD took longer to appear, 15- and 22-month CHL2(Q150/Q150), 18-month Hdh(Q92/Q92) and 2-year-old YAC128 animals also exhibited significant HD-like mRNA signatures. Whereas it was expected that the expression of full-length huntingtin transprotein might result in unique gene expression changes compared with those caused by the expression of an N-terminal huntingtin fragment, no discernable differences between full-length and fragment models were detected. In addition, very high correlations between the signatures of mice expressing normal levels of wild-type huntingtin and mice in which the wild-type protein is absent suggest a limited effect of the wild-type protein to change basal gene expression or to influence the qualitative disease-related effect of mutant huntingtin. The combined analysis of mouse and human HD transcriptomes provides important temporal and mechanistic insights into the process by which mutant huntingtin kills striatal neurons. In addition, the discovery that several available lines of HD mice faithfully recapitulate the gene expression signature of the human disorder provides a novel aspect of validation with respect to their use in preclinical therapeutic trials. Experiment Overall Design: Striatal samples from 4 R6/2 mutant mice (12 weeks-old) and 5 age-matched wild-type mice.

2008-06-16 | E-GEOD-9803 | biostudies-arrayexpress

Gene expression data from cortex of 9 week old wild type, R6/2, HDAC4het and R6/2::HDAC4het mice

Project description:Histone deacetylase (HDAC) 4 is a transcriptional repressor that contains a glutamine rich domain. We hypothesised that it may be involved in the molecular pathogenesis of Huntington's disease (HD), a protein folding neurodegenerative disorder caused by an aggregation-prone polyglutamine expansion and transcriptional dysregulation. We found that HDAC4 interacts with huntingtin in a polyglutamine-length dependent manner and co-localises with cytoplasmic inclusions. We show that HDAC4 reduction delayed cytoplasmic aggregate formation, restored Bdnf transcript levels and rescued neuronal and cortico-striatal synaptic function in HD mouse models. This was accompanied by an improvement in motor co-ordination, neurological phenotypes and increased lifespan. Surprisingly, HDAC4 reduction had no effect on global transcriptional dysfunction and did not modulate nuclear huntingtin aggregation. Our results define a crucial role for cytoplasmic aggregation in the molecular pathology of HD. HDAC4 reduction presents a novel strategy for targeting huntingtin aggregation which may be amenable to small molecule therapeutics. mRNA expression analysis was performed by microarray in 9 weeks old WT (n=9), R6/2 (n=9), HDAC4het (n=9) and Double R6/2::HDAC4het (n=10) mice. Microarray quality control was performed using the software package provided on RACE (http://race.unil.ch).

2014-10-10 | E-GEOD-38218 | biostudies-arrayexpress

Gene expression data from cortex of 15 week old wild type, R6/2, HDAC4het and R6/2::HDAC4het mice

Project description:Histone deacetylase (HDAC) 4 is a transcriptional repressor that contains a glutamine rich domain. We hypothesised that it may be involved in the molecular pathogenesis of Huntington's disease (HD), a protein folding neurodegenerative disorder caused by an aggregation-prone polyglutamine expansion and transcriptional dysregulation. We found that HDAC4 interacts with huntingtin in a polyglutamine-length dependent manner and co-localises with cytoplasmic inclusions. We show that HDAC4 reduction delayed cytoplasmic aggregate formation, restored Bdnf transcript levels and rescued neuronal and cortico-striatal synaptic function in HD mouse models. This was accompanied by an improvement in motor co-ordination, neurological phenotypes and increased lifespan. Surprisingly, HDAC4 reduction had no effect on global transcriptional dysfunction and did not modulate nuclear huntingtin aggregation. Our results define a crucial role for cytoplasmic aggregation in the molecular pathology of HD. HDAC4 reduction presents a novel strategy for targeting huntingtin aggregation which may be amenable to small molecule therapeutics. mRNA expression analysis was performed by microarray in 15 weeks old WT (n=8), R6/2 (n=9), HDAC4het (n=8) and Double R6/2::HDAC4het (n=9) mice. Microarray quality control was performed using the software package provided on RACE (http://race.unil.ch).

2014-10-10 | E-GEOD-38219 | biostudies-arrayexpress

R6/1 brain hemisphere time series gene expression

Project description:HD R6/1 transgenic mouse line brain hemispheres dissected. RNA targets were created for transgenics and wildtypes at time points 18, 22 and 27 weeks. Profiles and data analysis performed using the Bioconductor software and linear model contrasts using LIMMA on RMA probeset summarys. Keywords: timecourse

2007-07-31 | GSE3621 | GEO

Kynurenine treatment of herpesivrus stimulated iCD103 dendritic cells

Project description:We report the gene expression (obtained by next generation RNAseq) of inducible CD103+ dendritic cells, iCD103 cells, stimulated with both murine herpesvirus-68 and the immunomodulatory tryptophan derivative kynurenine (kyn). This study provides data on how tryptophan derivatives can modulate pro-inflammatory cytokine expression in virus treated dendritic cells.

2021-01-01 | GSE160307 | GEO

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