Effect of WS974536 on astrocyte proteomics
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ABSTRACT:
ORGANISM(S): Mus Musculus
SUBMITTER: 
Xu Qi
PROVIDER: PXD055494 | iProX | Tue Sep 03 00:00:00 BST 2024
REPOSITORIES: iProX
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Project description:MartínJiménez2017 - Genome-scale reconstruction of the human astrocyte metabolic network
This model is described in the article:
Genome-Scale Reconstruction
of the Human Astrocyte Metabolic Network.
Martín-Jiménez CA,
Salazar-Barreto D, Barreto GE, González J.
Front Aging Neurosci 2017; 9: 23
Abstract:
Astrocytes are the most abundant cells of the central
nervous system; they have a predominant role in maintaining
brain metabolism. In this sense, abnormal metabolic states have
been found in different neuropathological diseases.
Determination of metabolic states of astrocytes is difficult to
model using current experimental approaches given the high
number of reactions and metabolites present. Thus, genome-scale
metabolic networks derived from transcriptomic data can be used
as a framework to elucidate how astrocytes modulate human brain
metabolic states during normal conditions and in
neurodegenerative diseases. We performed a Genome-Scale
Reconstruction of the Human Astrocyte Metabolic Network with
the purpose of elucidating a significant portion of the
metabolic map of the astrocyte. This is the first global
high-quality, manually curated metabolic reconstruction network
of a human astrocyte. It includes 5,007 metabolites and 5,659
reactions distributed among 8 cell compartments,
(extracellular, cytoplasm, mitochondria, endoplasmic reticle,
Golgi apparatus, lysosome, peroxisome and nucleus). Using the
reconstructed network, the metabolic capabilities of human
astrocytes were calculated and compared both in normal and
ischemic conditions. We identified reactions activated in these
two states, which can be useful for understanding the
astrocytic pathways that are affected during brain disease.
Additionally, we also showed that the obtained flux
distributions in the model, are in accordance with
literature-based findings. Up to date, this is the most
complete representation of the human astrocyte in terms of
inclusion of genes, proteins, reactions and metabolic pathways,
being a useful guide for in-silico analysis of several
metabolic behaviors of the astrocyte during normal and
pathologic states.
This model is hosted on
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MODEL1608180000.
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2017-05-18 | MODEL1608180000 | BioModels
Project description:Disease, injury, and aging induce pathological reactive astrocyte states that contribute to neurodegeneration. Modulating reactive astrocytes therefore represents an attractive therapeutic strategy. Here, we describe the development of an astrocyte phenotypic screening platform for identifying chemical modulators of astrocyte reactivity. Leveraging this platform for chemical screening, we identify HDAC3 inhibitors as effective suppressors of pathological astrocyte reactivity. We demonstrate that HDAC3 inhibition reduces molecular and functional characteristics of reactive astrocytes in vitro. Transcriptional and chromatin mapping studies show that HDAC3 inhibition disarms pathological astrocyte gene expression and function while promoting the expression of genes associated with beneficial astrocytes. Administration of RGFP966, a small molecule HDAC3 inhibitor, blocks reactive astrocyte formation and promotes neuroprotection in vivo in mice. Collectively, these results establish a platform for discovering modulators of reactive astrocyte states, inform the mechanisms that control astrocyte reactivity, and demonstrate the therapeutic benefits of modulating astrocyte reactivity for neurodegenerative diseases.
2024-01-10 | GSE185605 | GEO
Project description:Disease, injury, and aging induce pathological reactive astrocyte states that contribute to neurodegeneration. Modulating reactive astrocytes therefore represents an attractive therapeutic strategy. Here, we describe the development of an astrocyte phenotypic screening platform for identifying chemical modulators of astrocyte reactivity. Leveraging this platform for chemical screening, we identify HDAC3 inhibitors as effective suppressors of pathological astrocyte reactivity. We demonstrate that HDAC3 inhibition reduces molecular and functional characteristics of reactive astrocytes in vitro. Transcriptional and chromatin mapping studies show that HDAC3 inhibition disarms pathological astrocyte gene expression and function while promoting the expression of genes associated with beneficial astrocytes. Administration of RGFP966, a small molecule HDAC3 inhibitor, blocks reactive astrocyte formation and promotes neuroprotection in vivo in mice. Collectively, these results establish a platform for discovering modulators of reactive astrocyte states, inform the mechanisms that control astrocyte reactivity, and demonstrate the therapeutic benefits of modulating astrocyte reactivity for neurodegenerative diseases.
2024-01-10 | GSE185212 | GEO
Project description:Disease, injury, and aging induce pathological reactive astrocyte states that contribute to neurodegeneration. Modulating reactive astrocytes therefore represents an attractive therapeutic strategy. Here, we describe the development of an astrocyte phenotypic screening platform for identifying chemical modulators of astrocyte reactivity. Leveraging this platform for chemical screening, we identify HDAC3 inhibitors as effective suppressors of pathological astrocyte reactivity. We demonstrate that HDAC3 inhibition reduces molecular and functional characteristics of reactive astrocytes in vitro. Transcriptional and chromatin mapping studies show that HDAC3 inhibition disarms pathological astrocyte gene expression and function while promoting the expression of genes associated with beneficial astrocytes. Administration of RGFP966, a small molecule HDAC3 inhibitor, blocks reactive astrocyte formation and promotes neuroprotection in vivo in mice. Collectively, these results establish a platform for discovering modulators of reactive astrocyte states, inform the mechanisms that control astrocyte reactivity, and demonstrate the therapeutic benefits of modulating astrocyte reactivity for neurodegenerative diseases.
2024-01-10 | GSE184437 | GEO
Project description:Disease, injury, and aging induce pathological reactive astrocyte states that contribute to neurodegeneration. Modulating reactive astrocytes therefore represents an attractive therapeutic strategy. Here, we describe the development of an astrocyte phenotypic screening platform for identifying chemical modulators of astrocyte reactivity. Leveraging this platform for chemical screening, we identify HDAC3 inhibitors as effective suppressors of pathological astrocyte reactivity. We demonstrate that HDAC3 inhibition reduces molecular and functional characteristics of reactive astrocytes in vitro. Transcriptional and chromatin mapping studies show that HDAC3 inhibition disarms pathological astrocyte gene expression and function while promoting the expression of genes associated with beneficial astrocytes. Administration of RGFP966, a small molecule HDAC3 inhibitor, blocks reactive astrocyte formation and promotes neuroprotection in vivo in mice. Collectively, these results establish a platform for discovering modulators of reactive astrocyte states, inform the mechanisms that control astrocyte reactivity, and demonstrate the therapeutic benefits of modulating astrocyte reactivity for neurodegenerative diseases.
2024-01-10 | GSE231598 | GEO
Project description:Disease, injury, and aging induce pathological reactive astrocyte states that contribute to neurodegeneration. Modulating reactive astrocytes therefore represents an attractive therapeutic strategy. Here, we describe the development of an astrocyte phenotypic screening platform for identifying chemical modulators of astrocyte reactivity. Leveraging this platform for chemical screening, we identify HDAC3 inhibitors as effective suppressors of pathological astrocyte reactivity. We demonstrate that HDAC3 inhibition reduces molecular and functional characteristics of reactive astrocytes in vitro. Transcriptional and chromatin mapping studies show that HDAC3 inhibition disarms pathological astrocyte gene expression and function while promoting the expression of genes associated with beneficial astrocytes. Administration of RGFP966, a small molecule HDAC3 inhibitor, blocks reactive astrocyte formation and promotes neuroprotection in vivo in mice. Collectively, these results establish a platform for discovering modulators of reactive astrocyte states, inform the mechanisms that control astrocyte reactivity, and demonstrate the therapeutic benefits of modulating astrocyte reactivity for neurodegenerative diseases.
2024-01-10 | GSE230817 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below. Disease, injury, and aging induce pathological reactive astrocyte states that contribute to neurodegeneration. Modulating reactive astrocytes therefore represents an attractive therapeutic strategy. Here, we describe the development of an astrocyte phenotypic screening platform for identifying chemical modulators of astrocyte reactivity. Leveraging this platform for chemical screening, we identify HDAC3 inhibitors as effective suppressors of pathological astrocyte reactivity. We demonstrate that HDAC3 inhibition reduces molecular and functional characteristics of reactive astrocytes in vitro. Transcriptional and chromatin mapping studies show that HDAC3 inhibition disarms pathological astrocyte gene expression and function while promoting the expression of genes associated with beneficial astrocytes. Administration of RGFP966, a small molecule HDAC3 inhibitor, blocks reactive astrocyte formation and promotes neuroprotection in vivo in mice. Collectively, these results establish a platform for discovering modulators of reactive astrocyte states, inform the mechanisms that control astrocyte reactivity, and demonstrate the therapeutic benefits of modulating astrocyte reactivity for neurodegenerative diseases.
2024-01-10 | GSE185215 | GEO
Project description:Growing evidence implicates the importance of glia, particularly astrocytes, in neurological and psychiatric diseases. Here, we describe a rapid and robust method for the differentiation of highly pure populations of astrocytes from human induced pluripotent stem cells (hiPSCs), via a neural progenitor cell (NPC) intermediate. Using this method, we generated hiPSC-derived astrocyte populations (hiPSC-astrocytes) from 42 NPC lines (derived from 30 individuals) with an average of ~90% S100β-positive cells. Transcriptomic analysis demonstrated that the hiPSC-astrocytes are highly similar to primary human fetal astrocytes and characteristic of a non-reactive state. hiPSC-astrocytes respond to inflammatory stimulants, display phagocytic capacity and enhance microglial phagocytosis. hiPSC-astrocytes also possess spontaneous calcium transient activity. Our novel protocol is a reproducible, straightforward (single media) and rapid (<30 days) method to generate homogenous populations of hiPSC-astrocytes that can be used for neuron-astrocyte and microglia-astrocyte co-cultures for the study of neuropsychiatric disorders.
2017-08-18 | GSE97904 | GEO
Project description:During development of the mammalian central nervous system (CNS), neurons and glial cells (astrocytes and oligodendrocytes) are generated from common neural precursor cells (NPCs). However, neurogenesis precedes gliogenesis, which normally commences at later stages of fetal telencephalic development. Astrocyte differentiation of mouse NPCs at embryonic day (E) 14.5 (relatively late gestation) is induced by activation of the transcription factor STAT3, whereas at E11.5 (mid-gestation) NPCs do not differentiate into astrocytes even when stimulated by STAT3-activating cytokines such as leukemia inhibitory factor (LIF). This can be explained in part by the fact that astrocyte-specific gene promoters are highly methylated in NPCs at E11.5, but other mechanisms are also likely to play a role. We therefore sought to identify genes involved in the inhibition of astrocyte differentiation of NPCs at midgestation. We first examined gene expression profiles in E11.5 and E14.5 NPCs, using Affymetrix GeneChip analysis, applying the Percellome method to normalize gene expression level. We then conducted in situ hybridization analysis for selected genes found to be highly expressed in NPCs at midgestation. Among these genes, we found that N-myc and high mobility group AT-hook 2 (Hmga2) were highly expressed in the E11.5 but not the E14.5 ventricular zone of mouse brain, where NPCs reside. Transduction of N-myc and Hmga2 by retroviruses into E14.5 NPCs, which normally differentiate into astrocytes in response to LIF, resulted in suppression of astrocyte differentiation. However, sustained expression of N-myc and Hmga2 in E11.5 NPCs failed to maintain the hypermethylated status of an astrocyte-specific gene promoter. Taken together, our data suggest that astrocyte differentiation of NPCs is regulated not only by DNA methylation but also by genes whose expression is controlled spatio-temporally during brain development. Experiment Overall Design: Neuroepithelial cells(NPCs) were prepared from telencephalons of E11.5 and E14.5 mice and cultured in N2-supplemented Dulbecco's Modified Eagle's Medium with F12 (GIBCO) containing 10 ng/ml basic FGF (R&D Systems) (N2/DMEM/F12/bFGF) on culture dishes (Nunc) or chamber slide (Nunc) which had been precoated with poly-L-ornithine (Sigma) and fibronectin (Sigma). E11.5 NPCs were cultured for one day and E14.5 NPCs were for four days.
2008-10-20 | E-GEOD-10796 | biostudies-arrayexpress
Project description:Diverse subpopulations of astrocytes tile different brain regions to accommodate local requirements of neurons and associated neuronal circuits. Nevertheless, molecular mechanisms governing astrocyte diversity remain mostly unknown. We explored the role of a zinc finger transcription factor Yin Yang 1 (YY1) that is expressed in astrocytes. We found that specific deletion of YY1 from astrocytes causes severe motor deficits in mice, induces Bergmann gliosis, and results in simultaneous loss of GFAP expression in velate and fibrous cerebellar astrocytes. Single cell RNA-seq analysis showed that YY1 exerts specific effects on gene expression in subpopulations of cerebellar astrocytes. We found that although YY1 is dispensable for the initial stages of astrocyte development, it regulates subtype-specific gene expression during astrocyte maturation. Moreover, YY1 is continuously needed to maintain astrocyte identity in the adult cerebellum. Our findings suggest that YY1 plays critical roles regulating cerebellar astrocyte maturation during development and maintaining a mature phenotype of astrocytes in the adult cerebellum.
2022-04-01 | GSE166792 | GEO