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GSE68169
Mus musculus
24 Downloadable Samples
Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
A detailed knowledge of the mechanisms underlying brain aging is fundamental to understand its functional decline and the baseline upon which brain pathologies superimpose. Endogenous protective mechanisms must contribute to the adaptability and plasticity still present in the healthy aged brain. Apolipoprotein D (ApoD) is one of the few genes with a consistent and evolutionarily conserved up-regulation in the aged brain. ApoD protecting roles upon stress or injury are well known, but a study of the effects of ApoD expression in the normal aging process is still missing. Using an ApoD-knockout mouse we analyze the effects of ApoD on factors contributing to the functional maintenance of the aged brain. We focused our cellular and molecular analyses in cortex and hippocampus at an age representing the onset of senescence where mortality risks are below 25%, avoiding bias towards long-lived animals. Lack of ApoD causes a prematurely aged brain without altering lifespan. Age-dependent hyperkinesia and memory deficits are accompanied by differential molecular effects in cortex and hippocampus. Transcriptome analyses reveal distinct effects of ApoD loss on the molecular age-dependent patterns of cortex and hippocampus, with different cell-type contributions to age-regulated gene expression. Markers of glial reactivity, proteostasis, and oxidative and inflammatory damage reveal early signs of aging and enhanced brain deterioration in the ApoD-knockout brain. The lack of ApoD results in an age-enhanced significant reduction in neuronal calcium-dependent functionality markers and signs of early reduction of neuronal numbers in the cortex, thus impinging upon parameters clearly differentiating neurodegenerative conditions from healthy brain aging. Our data support the hypothesis that the physiological increased brain expression of ApoD represents a homeostatic anti-aging mechanism.
Publication Title
Aging without Apolipoprotein D: Molecular and cellular modifications in the hippocampus and cortex.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples- Mus musculus
- 17 Downloadable Samples
Illumina HiSeq 2500
Description
Recent pre-clinical and clinical evidences indicate that hematopoietic stem and progenitor cells (HSPCs) and/or their progeny can serve as vehicles for therapeutic molecule delivery across the blood brain barrier by contributing to the turnover of myeloid cell populations in the brain. However, the differentiation and functional characteristics of the cells reconstituted after transplantation are still to be determined, and in particular whether bona fide microglia could be reconstituted by the donor cell progeny post-transplant to be assessed. We here firstly demonstrate that HSPC transplantation can generate transcriptionally-dependable new microglia through a stepwise process reminiscent of physiological post-natal microglia maturation. Hematopoietic cells able to generate new microglia upon transplantation into myeloablated recipients are retained within human and murine long-term hematopoietic stem cells (HSCs). Similar transcriptionally dependable new microglia cells can also be generated by intra-cerebral ventricular delivery of HSPCs. Importantly, this novel route is associated to a clinically relevant faster and more widespread microglia replacement compared to systemic HSPC injection. Overall, this work supports the relevance and feasibility of employing HSPCs for renewing brain myeloid and microglia cells with new populations endowed with the ability to exert therapeutic effects in the central nervous system, and identifies novel modalities, such as transplantation of enriched stem cell fractions and direct brain delivery of HSPCs, for increasing the actual contribution of the transplanted cells to microgliosis and their therapeutic activity. Overall design: mRNA profiles of µ and TAµ myeloid brain populations were obtained in triplicate mice of Adult control, P10 control and Adult BU-treated mice after GFP Lin-transplantation (both µ and TAµ populations)
Publication Title
Intracerebroventricular delivery of hematopoietic progenitors results in rapid and robust engraftment of microglia-like cells.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Mus musculus
- 24 Downloadable Samples
- Affymetrix Mouse Gene 2.0 ST Array (mogene20st)
Description
Considering the numerous complex and different pathological mechanisms involved in Alzheimers disease (AD) progression, treatments targeting a single cause may lead to limited benefits. The goal of this study was the identification of a novel mode of action for this unmet need. Pharmacological tool compounds: suberoylanilide hydroxamic acid (SAHA) and tadalafil, targeting histone deacetylases (HDAC) and phosphodiesterase 5 (PDE5) respectively, were utilized simultaneously for in-vitro and in-vivo Proof-of-Concept (PoC). A synergistic effect was observed in the amelioration of AD signs using the combination therapy in Tg2576 mice. Finally, a therapeutic agent, CM-414, inhibiting simultaneously HDAC2/6 and PDE5 was generated and tested in Tg2576 mice. CM-414 reversed cognitive impairment, reduced amyloid and tau pathology, and rescued dendritic spine density loss in the hippocampus in AD mice. Importantly, the effect obtained was present after a 4-weeks wash-out period.
Publication Title
Concomitant histone deacetylase and phosphodiesterase 5 inhibition synergistically prevents the disruption in synaptic plasticity and it reverses cognitive impairment in a mouse model of Alzheimer's disease.
Sample Metadata Fields
Specimen part
View Samples- Danio rerio
- 20 Downloadable Samples
- IlluminaHiSeq2000
Description
Subclassification of lymphoid neoplasms is often based on the presumed cell of origin based on T and B progenitor gene expression and the effect of cell lineage on influencing functional characteristics such as aggression and self-renewal capacity is largely unknown, accounted for in part, by lack of experimental models to address these questions. Here, we have used transgenic zebrafish to create the first models of Myc-induced B-ALL and mixed phenotypic B/T-ALL, opening new avenues for studying the these leukemias in the zebrafish. Our work has utilized syngeneic strain zebrafish, limiting dilution cell transplantation, and the widely reported rag2-Myc transgenic model to provide new understanding of how strain differences can underlie leukemia onset in the zebrafish model. Even more importantly, our work now for the first time, has allowed assessment of cell lineage on dictating aggression and leukemia stem cell frequency independent of the underlying oncogenic driver. In total, our work uncoveres that T-ALLs are more aggressive and have higher numbers of leukemia stem cells when compared with B-ALL and mixed phenotypic ALL. Furthermore, analysis of our biphenotypic B/T-ALL suggests that B cell pathways lock cells in less aggressive and lower stem cell fates and are dominant in regulating these processes when T cell pathways are co-regulated within ALL cells. Overall design: The goal of our study is to determine the transcriptional profiles of high and low self-renewing capacity tumors. 20 samples total: 11 unique samples (9 samples with biological replicates), 6 high self-renewing tumors (>1% cells could initiate leukemia) and 5 low self-renewing tumors (<1% of cells could initiate leukemia).
Publication Title
Cell of origin dictates aggression and stem cell number in acute lymphoblastic leukemia.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 72 Downloadable Samples
- Illumina HiSeq 2500
Description
Regulation of gene expression is an important aspect of insulin's physiological action, however, most studies rely on in vitro systems or pharmacological doses of insulin. Here, we demonstrate that under euglycemic-clamp conditions, physiological levels of insulin regulate over 1500 transcripts in muscle and 1000 transcripts in liver. These include expected pathways related to glucose and lipid utilization, mitochondrial function and autophagy in muscle, and glucose production and steroidogenesis in liver, as well as unexpected pathways, such as mRNA splicing, chromatin remodeling, and regulation of hepatocyte nuclear factors. Insulin also regulates over 100 non-coding RNAs in muscle and liver. These changes in coding and non-coding RNAs, refined by alternative splicing, provide an integrated transcriptional network underlying the complexity of insulin action in vivo.
Publication Title
Multi-dimensional Transcriptional Remodeling by Physiological Insulin In Vivo.
Sample Metadata Fields
Sex, Age, Specimen part, Cell line, Time
View Samples- Homo sapiens
- 18 Downloadable Samples
- Affymetrix Human Genome U219 Array (hgu219)
Description
Crohn's Disease (CD) is a chronic inflammatory disease of the intestinal tract.
Publication Title
Commensal-Specific CD4(+) Cells From Patients With Crohn's Disease Have a T-Helper 17 Inflammatory Profile.
Sample Metadata Fields
Sex, Age, Disease, Subject
View Samples- Mus musculus
- 6 Downloadable Samples
- Illumina HiSeq 2500
Description
CNS-delivery of Interleukin 4 (IL-4) - via a lentiviral-mediated gene therapy strategy - skews microglia to proliferate, inducing these cells to adopt the phenotype of slowly proliferating cells. Transcriptome analysis revealed that IL-4-treated microglia express a broad number of genes normally encoded by embryonic microglia. Overall design: RNAseq analysis of sorted microglia from mice receiving IL-4 gene therapy
Publication Title
Interleukin 4 modulates microglia homeostasis and attenuates the early slowly progressive phase of amyotrophic lateral sclerosis.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Mus musculus
- 53 Downloadable Samples
- Illumina HiSeq 2500
Description
Comprehensive knowledge of the dynamic changes in the cardiac transciptome can inform disease mechanism. Previous transcriptome profiling studies on heart failure rely on either microarray or RNA-Seq with low coverage, leaving a large portion of the transcriptome unexplored. Additionally, previous studies only examined two end stages of the disease, onset and late-stage heart failure. Profile of the transcriptome in the middle stage of disease progression can reveal critical molecular events underlying disease transition. Towards these goals, we conducted a multi-factorial RNA-Seq experiment, comparing the dynamic changes in the transcriptome of two murine models of heart failure, pressure overload and loss of mitochondrial complex I. Our data represents the deepest transcriptome coverage to date, covering onset, progression, and late stage of the disease. We found extensive differences in the expression magnitude and dynamics of the transciptomes in different heart failure models. In addition, such differences are associated with progressive worsening of cardiac physiology. Our analysis revealed that mitochondrial dysfunction combined with stress leads to increased number of differentially expressed long intergenic noncoding RNAs, including a recently identified lincRNA that is a master regulator of the cardiac lineage during development. Overall design: Cardiac tissues were cleaned with PBS and harvested at 1, 2, 4, and 8 weeks after surgeries by freezing in liquid nitrogen. Cardiac RNA profiles of wild type (WT) and ndufs4H-/- mice after surgeries were generated by deep sequencing at 4 time points, in quadruplicate, using Illumina HiSeq2000. The three factors of the data are genetic (WT vs. ndufs4H-/-), environmental stress (trans-aortic constriction vs. Sham controls), and time (Week 1, Week 2, Week 4 and Week 8). Thus, there are 16 samples in total and each sample has 4 replicates.
Publication Title
Revealing Pathway Dynamics in Heart Diseases by Analyzing Multiple Differential Networks.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 20 Downloadable Samples
- Affymetrix Human Exon 1.0 ST Array [transcript (gene) version (huex10st)
Description
Myotonic Dystrophy Type-2 (DM2) is an autosomal dominant disease caused by the expansion of a CCTG tetraplet repeat. It is a multisystemic disorder, affecting skeletal muscles, the heart, the eye, the central nervous system and the endocrine system.
Publication Title
Genome wide identification of aberrant alternative splicing events in myotonic dystrophy type 2.
Sample Metadata Fields
Sex, Age, Specimen part, Disease, Disease stage
View Samples- Mus musculus
- 7 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Nuclear Protein 1 (Nupr1) is a major actor of the cell stress response required for KrasG12D-driven formation of pancreatic intraepithelial neoplastic (PanINs) lesions in mice. We investigated the impact of Nupr1-depletion on the development and biology of murin pancreatic adenocarcinomas (PDAC) in the Pdx1-cre;LSL-KrasG12D;Ink4a/Arffl/fl (KIC) mice. We found that only one half of Nupr1-deficient mice developed PDAC. This is related to increased caspase 3 activity and low IER3 expression in Nupr1-deficient;KIC in the pancreas. Moreover, when Nupr1-deficient;KIC mice do develop PDAC, tumors present with impaired epithelial-to-mesenchymal transition (EMT). Transcriptoma analysis revealed that Nupr1-deficient and Nupr1wt;KIC PDACs presented enrichment of gene signatures of the human classical- and quasi-mesenchymal (QM)-PDAC respectively. Moreover, Nupr1-deficient;KIC PDACs shared with human classical-PDACs overexpression of Kras-activation genes. In addition, cells derived from Nupr1-deficient;KIC PDACs formed fewer microspheres in vitro compared to Nupr1wt;KIC cells, indicative of stemness impairment in the absence of Nupr1. Finally, we found that Nupr1-deficient;KIC cells were more sensitive to some anticancer drugs than their Nupr1wt counterpart. Hence, this study establishes the pivotal role of Nupr1 in PDAC progression after PanIN and in PDAC EMT in vivo, with an impact in PDAC cell stemness. As a consequence, according to absence or presence of Nupr1, KIC mice develop tumors that phenocopy human classical- or QM-PDAC, respectively, thus becoming attractive models for preclinical drug trials.
Publication Title
Genetic inactivation of Nupr1 acts as a dominant suppressor event in a two-hit model of pancreatic carcinogenesis.
Sample Metadata Fields
Specimen part
View Samples