Connectivity mapping of a chronic kidney disease progression signature identified lysine deacetylases as novel therapeutic targets
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PROVIDER: PRJNA564530 | ENA |
REPOSITORIES: ENA
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Project description:Motivation and design: Renal tubulointerstitial injury is an important determinant of chronic kidney disease (CKD) progression, yet treatment is limited to renin angiotensin system blockade. Accordingly, we performed global expression profiling in a 2 × 2 factorial design (N = 8 in each group) on RNA extracted from male Col4a3–/– mice and littermate controls on a 129X1/SvJ background at 4 and 7 weeks of age. Col4a3–/– mice have a mutation in the gene encoding the α3 chain of type IV collagen, associated with proteinuria and progressive loss of kidney function. We analyzed expression with Affymetrix GeneChip Mouse Gene 2.0 ST Arrays and derived a novel CKD progression signature based on aging and disease in Col4a3–/– mice. Using our progression signature, we sought to repurpose existing drugs for the treatment of progressive CKD. Results: Computational drug repurposing with the Connectivity Map identified lysine deacetylase inhibitor, vorinostat, as a novel candidate treatment for this murine model of CKD. Treatment with vorinostat attenuated tubulointerstitial injury, fibrosis, and altered inflammation. Vorinostat administration significantly increased the lifespan of Col4a3–/– mice although effects on urinary albumin excretion, plasma creatinine, and blood urea nitrogen were modest. Conclusions: Our data suggest that expression profiling and computational drug repurposing can be used to identify novel drugs that may reverse gene expression changes in experimental CKD. Lysine deacetylase inhibition may be a novel treatment approach to CKD associated with proteinuria and progressive tubulointerstitial injury.
2020-01-31 | GSE137086 | GEO
Project description:Tumor microtubes (TMs) connect glioma cells to a network with considerable relevance for tumor progression and therapy resistance. The determination of TM-interconnectivity in individual tumors has been challenging and the impact on patient survival unresolved. Here, a connectivity signature from single-cell RNA-sequenced (scRNA-Seq) xenografted primary glioblastoma (GB) cells has been established using a dye uptake methodology, confirmed with recording of cellular calcium epochs and validated with clinical correlations. Astrocyte-like and mesenchymal-like GB cells have the highest connectivity signature scores in scRNA-sequenced patient-derived xenografts and patient samples. In large GB cohorts, network connectivity correlated with the mesenchymal subtype and dismal patient survival. CHI3L1 has been identified and validated as a robust molecular marker of connectivity with functional relevance. The connectivity signature allows novel insights into brain tumor biology, provides a proof-of-principle that tumor cell TM-connectivity is relevant for patients’ prognosis, and serves as a robust prognostic biomarker.
2023-11-27 | PXD044001 | Pride
Project description:Tumor microtubes (TMs) connect glioma cells to a network with considerable relevance for tumor progression and therapy resistance. The determination of TM-interconnectivity in individual tumors has been challenging and the impact on patient survival unresolved. Here, a connectivity signature from single-cell RNA-sequenced (scRNA-Seq) xenografted primary glioblastoma (GB) cells has been established using a dye uptake methodology, confirmed with recording of cellular calcium epochs and validated with clinical correlations. Astrocyte-like and mesenchymal-like GB cells have the highest connectivity signature scores in scRNA-sequenced patient-derived xenografts and patient samples. In large GB cohorts, network connectivity correlated with the mesenchymal subtype and dismal patient survival. CHI3L1 has been identified and validated as a robust molecular marker of connectivity with functional relevance. The connectivity signature allows novel insights into brain tumor biology, provides a proof-of-principle that tumor cell TM-connectivity is relevant for patients’ prognosis, and serves as a robust prognostic biomarker.
| EGAS00001007611 | EGA
Project description:Dosage dependent tumor suppression by histone deacetylases 1/2
2013-03-21 | E-MTAB-1448 | biostudies-arrayexpress
Project description:Due to an increasing problem of drug resistance among almost all parasites species ranging from protists to worms, there is an urgent need to explore new drug targets and their inhibitors to provide new and effective parasitic therapeutics. In this regard, there is growing interest in exploring known drug leads of human epigenetic enzymes as potential starting points to develop novel treatments for parasitic diseases. This approach of repurposing (starting with validated targets and inhibitors) is quite attractive since it has the potential to reduce the expense of drug development and accelerate the process of developing novel drug candidates for parasite control. Lysine deacetylases (KDACs) are among the most studied epigenetic drug targets of humans, and a broad range of small-molecule inhibitors for these enzymes have been reported. In this work, we identify the KDAC protein families in representative species across important classes of parasites, screen a compound library of 23 hydroxamate- or benzamide-based small molecules KDAC inhibitors, and report their activities against a range of parasitic species, including the pathogen of malaria (Plasmodium falciparum), kinetoplastids (Trypanosoma brucei and Leishmania donovani), and nematodes (Brugia malayi, Dirofilaria immitis and Haemonchus contortus). Compound activity against parasites is compared to that observed against the mammalian cell line (L929 mouse fibroblast) in order to determine potential parasite-versus-host selectivity). The compounds showed nanomolar to sub-nanomolar potency against various parasites, and some selectivity was observed within the small panel of compounds tested. The possible binding modes of the active compounds at the different protein target sites within different species were explored by docking to homology models to help guide the discovery of more selective, parasite-specific inhibitors. This current work supports previous studies that explored the use of KDAC inhibitors in targeting Plasmodium to develop new anti-malarial treatments, and also pioneers experiments with these KDAC inhibitors as potential new anthelminthics. The selectivity observed begins to address the challenges of targeting specific parasitic diseases while limiting host toxicity.
| S-EPMC4581690 | biostudies-literature
Project description:Aspirin, or acetylsalicylic acid is widely used to control pain, inflammation and fever. Important to this function is its ability to irreversibly acetylate cyclooxygenases at active site serines. Aspirin has the potential to acetylate other amino-acid side-chains, leading to speculation that aspirin-mediated lysine acetylation could explain some of its drug actions or side-effects. Using a labeled form of aspirin, aspirin-d3, we identified over 12000 sites of lysine acetylation from cultured human cells. Although aspirin amplifies acetylation signals at thousands of sites, cells tolerate aspirin mediated acetylation very well unless endogenous deacetylases are inhibited. Apart from a limited number of cellular proteins that are substantially acetylated under endogenous conditions, aspirin mediated acetylation leads to a large increase in the acetylation of many proteins even although they remain at very low stoichiometry. This reinforces the idea that a major function of cellular deacetylases is the suppression of non-specific or non-enzymatic protein acetylation.
2017-01-10 | PXD003530 | Pride
Project description:Aspirin, or acetylsalicylic acid is widely used to control pain, inflammation and fever. Important to this function is its ability to irreversibly acetylate cyclooxygenases at active site serines. Aspirin has the potential to acetylate other amino-acid side-chains, leading to speculation that aspirin-mediated lysine acetylation could explain some of its drug actions or side-effects. Using a labeled form of aspirin, aspirin-d3, we identified over 12000 sites of lysine acetylation from cultured human cells. Although aspirin amplifies acetylation signals at thousands of sites, cells tolerate aspirin mediated acetylation very well unless endogenous deacetylases are inhibited. Apart from a limited number of cellular proteins that are substantially acetylated under endogenous conditions, aspirin mediated acetylation leads to a large increase in the acetylation of many proteins even although they remain at very low stoichiometry. This reinforces the idea that a major function of cellular deacetylases is the suppression of non-specific or non-enzymatic protein acetylation.
2017-03-29 | MSV000080778 | MassIVE
Project description:Truncating CHD8 mutations are amongst the highest confidence risk factors for autism spectrum disorders (ASD) identified to date. Here, we report that Chd8 heterozygous mice display increased brain size, motor delay, hypertelorism, pronounced hypoactivity, and anomalous responses to social stimuli. Whereas gene expression in the neocortex is only mildly affected at mid gestation, over 600 genes are differentially expressed in the early postnatal neocortex. Genes involved in cell adhesion and axon guidance are particularly prominent amongst the downregulated transcripts. Resting-state functional MRI identified increased synchronized activity in corticohippocampal and auditory-parietal networks in Chd8 heterozygous mutant mice, implicating altered connectivity as a potential mechanism underlying the behavioral phenotypes. Together, these data suggest that altered brain growth and diminished expression of important neurodevelopmental genes that regulate long-range brain wiring are followed by distinctive anomalies in functional brain connectivity in Chd8 +/− mice. Human imaging studies have reported altered functional connectivity in ASD patients, with long-range under-connectivity seemingly more frequent. Our data suggest that CHD8 haploinsufficiency represents a specific subtype of ASD where neuropsychiatric symptoms are underpinned by long-range over-connectivity.
2018-04-24 | GSE81103 | GEO
Project description:Aspirin, or acetylsalicylic acid is widely used to control pain, inflammation and fever. Important to this function is its ability to irreversibly acetylate cyclooxygenases at active site serines. Aspirin has the potential to acetylate other amino-acid side-chains, leading to speculation that aspirin-mediated lysine acetylation could explain some of its drug actions or side-effects. Using a labeled form of aspirin, aspirin-d3, we identified over 12000 sites of lysine acetylation from cultured human cells. Although aspirin amplifies acetylation signals at thousands of sites, cells tolerate aspirin mediated acetylation very well unless endogenous deacetylases are inhibited. Apart from a limited number of cellular proteins that are substantially acetylated under endogenous conditions, aspirin mediated acetylation leads to a large increase in the acetylation of many proteins even although they remain at very low stoichiometry. This reinforces the idea that a major function of cellular deacetylases is the suppression of non-specific or non-enzymatic protein acetylation.
2016-12-24 | PXD004995 | Pride
Project description:Aspirin, or acetylsalicylic acid is widely used to control pain, inflammation and fever. Important to this function is its ability to irreversibly acetylate cyclooxygenases at active site serines. Aspirin has the potential to acetylate other amino-acid side-chains, leading to speculation that aspirin-mediated lysine acetylation could explain some of its drug actions or side-effects. Using a labeled form of aspirin, aspirin-d3, we identified over 12000 sites of lysine acetylation from cultured human cells. Although aspirin amplifies acetylation signals at thousands of sites, cells tolerate aspirin mediated acetylation very well unless endogenous deacetylases are inhibited. Apart from a limited number of cellular proteins that are substantially acetylated under endogenous conditions, aspirin mediated acetylation leads to a large increase in the acetylation of many proteins even although they remain at very low stoichiometry. This reinforces the idea that a major function of cellular deacetylases is the suppression of non-specific or non-enzymatic protein acetylation.
2017-03-31 | MSV000080852 | MassIVE