MTOR Signaling is a Key Modifier and Therapeutic Target in a Mouse Model of X-linked Alport Syndrome.
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE338462 | GEO | 2026/07/13
REPOSITORIES: GEO
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Project description:Background: Increased concentrations of neuroblastoma suppressor of tumorgenicity 1 (NBL1) in the blood have been associated with disease progression in diabetic kidney disease and IgA nephropathy. However, it is unclear whether NBL1 is a causal factor for kidney disease and what is driving these increased concentrations in the blood. Methods: We tested causality of NBL1 by knocking out Nbl1 in two different mouse models of kidney disease (X-linked Alport Syndrome (XLAS) and low-dose cisplatin treatment) and performed a genetic analysis for the drivers of NBL1 concentrations in two independent cohorts of genetically diverse (DO) mice with X-linked Alport Syndrome (DO-XLAS). Results: Significant correlations were found between NBL1 concentrations in the blood and both GFR and ACR in DO-XLAS mice. However, XLAS mice with only one functional Nbl1 allele and reduced NBL1 concentrations had similar GFR and ACR compared to Nbl1 wildtype animals. Similarly, there was no difference between animals with one or two functional Nbl1 alleles after chronic low-dose cisplatin treatment. Genetic analysis of NBL1 concentrations in our DO-XLAS cohorts identified associations with loci on Chromosomes 4 and 17, with Clcnka, and MHC2 as potential candidates. Conclusion: Increased NBL1 in blood is a marker for different forms of kidney disease but is not a causal factor.
2025-11-22 | GSE310901 | GEO
Project description:Background: Increased concentrations of neuroblastoma suppressor of tumorgenicity 1 (NBL1) in the blood have been associated with disease progression in diabetic kidney disease and IgA nephropathy. However, it is unclear whether NBL1 is a causal factor for kidney disease and what is driving these increased concentrations in the blood. Methods: We tested causality of NBL1 by knocking out Nbl1 in two different mouse models of kidney disease (X-linked Alport Syndrome (XLAS) and low-dose cisplatin treatment) and performed a genetic analysis for the drivers of NBL1 concentrations in two independent cohorts of genetically diverse (DO) mice with X-linked Alport Syndrome (DO-XLAS). Results: Significant correlations were found between NBL1 concentrations in the blood and both GFR and ACR in DO-XLAS mice. However, XLAS mice with only one functional Nbl1 allele and reduced NBL1 concentrations had similar GFR and ACR compared to Nbl1 wildtype animals. Similarly, there was no difference between animals with one or two functional Nbl1 alleles after chronic low-dose cisplatin treatment. Genetic analysis of NBL1 concentrations in our DO-XLAS cohorts identified associations with loci on Chromosomes 4 and 17, with Clcnka, and MHC2 as potential candidates. Conclusion: Increased NBL1 in blood is a marker for different forms of kidney disease but is not a causal factor.
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The primary measurement will be assessment of kidney function at follow up relative to kidney function at inclusion. Kidney function will be evaluated by means of intravenous renography and GFR (glomerular filtration rate). A reduction in kidney function of 10% in one side measured by renography will be regarded as indicative of ureteral stenosis and a reduction of GFR 25% will indicate bilateral reduction/stenosis. . The kidney function will be assessed by intravenous renography and Glomerular Filtration Rate (GRF) at follow up after 2-3 months and 1 year after discharge.
Primary endpoints: The primary measurement will be assessment of kidney function at follow up relative to kidney function at inclusion. Kidney function will be evaluated by means of intravenous renography and GFR (glomerular filtration rate). A reduction in kidney function of 10% in one side measured by renography will be regarded as indicative of ureteral stenosis and a reduction of GFR 25% will indicate bilateral reduction/stenosis. . The kidney function will be assessed by intravenous renography and Glomerular Filtration Rate (GRF) at follow up after 2-3 months and 1 year after discharge. These two tests are chosen for evaluation of kidney function as they are the tests with a high level of evidence. All patients with reduced kidney function shown in one or both tests will be evaluated whether the reduction is caused by stenosis or other reasons (infections etc.).
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Project description:Phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway activation contributes to mantle cell lymphoma (MCL) pathogenesis and drug resistance. However, the use of mTOR inhibitors as single agents have shown limited clinical efficacy in relation with drug activation of feedback loops. Selective PI3K inhibition or dual PI3K/mTOR catalytic inhibition are different therapeutic approaches developed to achieve effective pathway blockage. Here, we evaluated the antitumor activity of a mTOR inhibitor, a pan-PI3K inhibitor and a dual PI3K/mTOR inhibitor in primary MCL cells. We found that dual PI3K/mTOR inhibitor modulated angiogenesis, tumor invasiveness and cytokine signaling compared to a mTOR inhibitor and a pan-PI3K inhibitor in MCL. We used microarrays to compare the effect of these three compounds in MCL and identified distinct classes of down-regulated genes modulated by each compound.
2013-12-14 | GSE53309 | GEO
Project description:The mTOR (mammalian Target of Rapamycin) pathway is constitutively activated in Diffuse Large B-Cell Lymphoma (DLBCL). mTOR inhibition has been shown to have clinical activity in patients with DLBCL, although overall response rates remain low. We therefore evaluated differences in the transcriptome between DLBCL cell lines with differential sensitivity to the mTOR inhibitor Rapamycin, to (A) identify gene-expression patterns(GEP) capable of identifying sensitivity to Rapamycin, (B) understand the underlying mechanisms of resistance to Rapamycin in DLBCL and (C) identify bioactive molecules likely to synergize with mTOR inhibitors. Using Affymetrix HuGene ST 1.0 microarrays, we were able to identify a gene expression signature capable of accurately predicting sensitivity and resistance to Rapamycin in DLBCL cell lines. Pathway analysis identified the serine/threonine kinase Akt as central to the differentially-expressed gene network. Connectivity mapping of our datasets identified compounds targeting the AKT pathway with a high likelihood of reversing the GEP associated with resistance to Rapamycin. Specifically, we evaluated the HIV protease inhibitor (PI) Nelfinavir, which is known to have anti-cancer and Akt-inhibitory properties, as well as the small molecule Akt inhibitor MK-2206, for their potential to synergize with to Rapamycin in DLBCL. Nelfinavir and MK-2206 caused profound inhibition of cell viability in combination with Rapamycin in DLBCL cell lines. Low nanomolar concentrations of Rapamycin inhibited phosphorylation of Akt and also downstream targets of activated mTOR when used in combination with these Akt inhibitors. These findings have the potential to significantly improve patient selection for mTOR inhibitor therapy, and to improve rates and depths of response. More broadly, they support the use of global RNA expression and connectivity mapping to improve patient selection and identify synergistic drug combinations for cancer therapy. DLBCL cell lines were tested for Rapamycin sensitivity and classified as "sensitive" or "resistant." Genome-wide analysis of all cell lines were performed using the Affymetrix HuGene ST 1.0 Array Platform. Genes with differential expression between sensitive and resistant cell lines were analyzed using Statistical Analysis of Microarrays (SAM) software, and a signature of genes determnined. This signature was found to accurately predict sensitivity or resistance of other DLBCL cell lines, and to identify the protein kinase Akt as central to resistance.
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Project description:Mosca2012 - Central Carbon Metabolism Regulated by AKT
The role of the PI3K/Akt/PKB signalling pathway in oncogenesis has been extensively investigated and altered expression or mutations of many components of this pathway have been implicated in human cancers. Indeed, expression of constitutively active forms of Akt/PKB can prevent cell death upon growth factor withdrawal. PI3K/Akt/mTOR-mediated survival relies on a profound metabolic adaptation, including aerobic glycolysis. Here, the link between the PI3K/Akt/mTOR pathway, glycolysis, lactic acid production and nucleotide biosynthesis has been modelled, considering two states - high and low PI3K/Akt/mTOR activity. The high PI3K/Akt/mTOR activity represents cancer cell line where PI3K/Akt/mTOR promotes a high rate of glucose metabolism (condition H) and the low PI3K/Akt/mTOR activity is characterised by a lower glycolytic rate due to a reduced PI3K/Akt/mTOR signal (condition L). This model corresponds to the high PI3K/Akt/mTOR signal (condition H).
This model is described in the article:
Computational Modelling of the Metabolic States Regulated by the Kinase Akt.
Mosca E, Alfieri R, Maj C, Bevilacqua A, Canti G, Milanesi L.
Frontiers in Systems Biology. 2012 Oct 13
Abstract:
Signal transduction pathways and gene regulation determine a major reorganization of metabolic activities in order to support cell proliferation. Protein Kinase B (PKB), also known as Akt, participates in the PI3K/Akt/mTOR pathway, a master regulator of aerobic glycolysis and cellular biosynthesis, two activities shown by both normal and cancer proliferating cells. Not surprisingly considering its relevance for cellular metabolism, Akt/PKB is often found hyperactive in cancer cells. In the last decade, many efforts have been made to improve the understanding of the control of glucose metabolism and the identification of a therapeutic window between proliferating cancer cells and proliferating normal cells. In this context, we have modelled the link between the PI3K/Akt/mTOR pathway, glycolysis, lactic acid production and nucleotide biosynthesis. We used a computational model in order to compare two metabolic states generated by the specific variation of the metabolic fluxes regulated by the activity of the PI3K/Akt/mTOR pathway. One of the two states represented the metabolism of a growing cancer cell characterised by aerobic glycolysis and cellular biosynthesis, while the other state represented the same metabolic network with a reduced glycolytic rate and a higher mitochondrial pyruvate metabolism, as reported in literature in relation to the activity of the PI3K/Akt/mTOR. Some steps that link glycolysis and pentose phosphate pathway revealed their importance for controlling the dynamics of cancer glucose metabolism.
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2024-09-02 | BIOMD0000000426 | BioModels