Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA119277 | ENA |
REPOSITORIES: ENA
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Project description:Spinocerebellar ataxia type 3 is a neurodegenerative disorder caused by the expansion of the polyglutamine repeat region within the ataxin-3 protein. The mutant protein forms intracellular aggregates in the brain. However, the cellular mechanisms causing toxicity are still poorly understood and there are currently no effective treatments. In this study we show that administration of a rapamycin ester, CCI-779, improves motor performance in a transgenic mouse model of SCA3. CCI-779 inhibits mammalian target of rapamycin (mTOR) and hence upregulates protein degradation by autophagy. CCI-779 reduces the number of aggregates seen in the brains of transgenic mice and decreases levels of cytosolic soluble mutant ataxin-3, while endogenous wild-type protein levels remain unaffected. CCI-779 is designed for long-term use in patients and therefore represents a possible therapeutic strategy for the treatment of SCA3. Using this disease model and treatment paradigm we employed a microarray approach to investigate transcriptional changes that might be important in the pathogenesis of SCA3. This approach identified Usp15, which showed expression changes at both the mRNA and protein level. Usp15 levels were also changed in mice expressing another mutant polyglutamine protein, huntingtin. In total we identified 16 transcripts that were decreased in transgenic ataxin-3 mice that were normalised following CCI-779 treatment, as the number of transcripts changed was low and the magnitude of these changes was small we suggest that transcriptional dysregulation may not be an important step in the primary pathogenesis of SCA3. Experiment Overall Design: We analyzed 19 brain samples in total. 4 samples from wt animals after placebo treatment. 5 samples from wt animals after CCI-779 treatment. 5 samples from SCA3 tg animals after placebo treatment. 5 samples from SCA3 tg animals after CCI-779 treatment.
2009-09-18 | E-GEOD-17994 | biostudies-arrayexpress
Project description:Spinocerebellar ataxia type 3 is a neurodegenerative disorder caused by the expansion of the polyglutamine repeat region within the ataxin-3 protein. The mutant protein forms intracellular aggregates in the brain. However, the cellular mechanisms causing toxicity are still poorly understood and there are currently no effective treatments. In this study we show that administration of a rapamycin ester, CCI-779, improves motor performance in a transgenic mouse model of SCA3. CCI-779 inhibits mammalian target of rapamycin (mTOR) and hence upregulates protein degradation by autophagy. CCI-779 reduces the number of aggregates seen in the brains of transgenic mice and decreases levels of cytosolic soluble mutant ataxin-3, while endogenous wild-type protein levels remain unaffected. CCI-779 is designed for long-term use in patients and therefore represents a possible therapeutic strategy for the treatment of SCA3. Using this disease model and treatment paradigm we employed a microarray approach to investigate transcriptional changes that might be important in the pathogenesis of SCA3. This approach identified Usp15, which showed expression changes at both the mRNA and protein level. Usp15 levels were also changed in mice expressing another mutant polyglutamine protein, huntingtin. In total we identified 16 transcripts that were decreased in transgenic ataxin-3 mice that were normalised following CCI-779 treatment, as the number of transcripts changed was low and the magnitude of these changes was small we suggest that transcriptional dysregulation may not be an important step in the primary pathogenesis of SCA3.
2009-09-12 | GSE17994 | GEO
Project description:Gene expression profiling of human glioma cell line LN-308. Cells were treated with the mTOR inhibitor CCI-779 or irradiated with a single dose of 4 Gy or a combination of both. The objective of this studywas to evaluate CCI-779 as a radio-sensitizing agent and to elucidate the underlying mechanisms. Irradiated, CCI-779-, DMSO- (vehicle control) or combination treated LN-308 samples were hybridized against pooled untreated LN-308 samples as reference (CCI+Irradiation vs. Ref; CCI vs. Ref; DMSO+Irradiation vs Ref; DMSO vs. Ref).Three independent replicates were generated for each treatment and control, respectively.
2011-09-19 | E-GEOD-24232 | biostudies-arrayexpress
Project description:Clinical Pharmacogenomics study. Renal Cell Carcinoma subjects were treated with CCI-779 and peripheral blood mononuclear cells were profiled over time of treatment. Population pharmacokinetics of CCI-779: Correlations to safety and pharmacogenomics responses in patients with advanced renal cancer. Clin Pharm Therapeutics Dec 2004 Keywords: other
2004-12-01 | GSE1982 | GEO
Project description:Gene expression profiling of human glioma cell line LN-308. Cells were treated with the mTOR inhibitor CCI-779 or irradiated with a single dose of 4 Gy or a combination of both. The objective of this studywas to evaluate CCI-779 as a radio-sensitizing agent and to elucidate the underlying mechanisms.
2011-09-20 | GSE24232 | GEO
Project description:The cholecystokinin B (2) receptor knockout (Cckbr KO) protects against allodynia induced by chronic constriction injury (CCI). The mechanism of this phenomenon is unknown, but must involve persistent changes in pain modulation and/or inflammatory pathways. We performed a gene expression study in two brain areas (midbrain and medulla) after surgical induction of CCI in Cckbr KO and wild-type (wt) control mice. The patterns of gene expression differences suggest that the immune system is activated in higher brain structures following CCI in the wt mice. The strongest differences include genes related to the MAPK pathway activation and cytokine production. In Cckbr KO mice this expressional pattern was absent. In addition, we found significant elevation of the Toll-like receptor 4 (Tlr4) in the supraspinal structures of the mice with deleted Cckbr compared to wt control mice. This up-regulation is most likely induced by the deletion of Cckbr. We suggest that there is a functional deficiency in the Tlr4 pathway which disables the development of neuropathic pain in Cckbr KO mice. Indeed, real time PCR analysis detected a CCI-induced upregulation of Tlr4 and Il1b expression in the lumbar region of wt but not Cckbr KO mice. Gene expression profiling indicates that elements of the immune response are not activated in Cckbr KO mice following CCI. Our findings suggest that there may be a role for CCK in the regulation of innate immunity. Experiment Overall Design: 32 chips altogether, 4 mutant mice sham-operated, 4 control mice sham-operated, 4 mutant mice CCI-operated, 4 control mice CCI-operated, midbarin and medulla samples from each animals
2008-06-16 | E-GEOD-9594 | biostudies-arrayexpress
Project description:This study analyzed the effect of RBM5 gene deletion in cortical brain tissue on differential gene expression/splicing changes 48h after a traumatic brain injury (TBI). TBI was induced in WT vs. KO mice by controlled cortical impact (CCI) injury. The four grouops included: (1) Sham-WT, (2) CCI-WT, (3) Sham-KO, and (4) CCI-KO. The objective of this study was to test if RBM5 KO decreased the expression of cell death mediators in the contused brain 48h post-injury.
2021-05-12 | GSE128543 | GEO
Project description:Human glioma cells treated with irradiation and/or CCI-779
| PRJNA132927 | ENA
Project description:The cholecystokinin B (2) receptor knockout (Cckbr KO) protects against allodynia induced by chronic constriction injury (CCI). The mechanism of this phenomenon is unknown, but must involve persistent changes in pain modulation and/or inflammatory pathways. We performed a gene expression study in two brain areas (midbrain and medulla) after surgical induction of CCI in Cckbr KO and wild-type (wt) control mice. The patterns of gene expression differences suggest that the immune system is activated in higher brain structures following CCI in the wt mice. The strongest differences include genes related to the MAPK pathway activation and cytokine production. In Cckbr KO mice this expressional pattern was absent. In addition, we found significant elevation of the Toll-like receptor 4 (Tlr4) in the supraspinal structures of the mice with deleted Cckbr compared to wt control mice. This up-regulation is most likely induced by the deletion of Cckbr. We suggest that there is a functional deficiency in the Tlr4 pathway which disables the development of neuropathic pain in Cckbr KO mice. Indeed, real time PCR analysis detected a CCI-induced upregulation of Tlr4 and Il1b expression in the lumbar region of wt but not Cckbr KO mice. Gene expression profiling indicates that elements of the immune response are not activated in Cckbr KO mice following CCI. Our findings suggest that there may be a role for CCK in the regulation of innate immunity. Keywords: genetic modification, neuropathic model, chronic constriction injury
2007-11-16 | GSE9594 | GEO