Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1034655 | ENA |
REPOSITORIES: ENA
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Project description:GLP-1 analogues, such as exendin-4, preserve functional β-cell mass in various model systems and are revolutionising management of type 2 diabetes. Yet, comparatively little is known about effectiveness in the face of severe β-cell depletion. Moreover, direct and sequential effects of exendin-4 on islet-specific gene expression over time in vivo are not well characterised. To address these issues and others, we have examined the time-dependent effects of exendin-4 treatment on β-cell mass regulation alongside accompanying changes in islet gene expression in vivo. Context-dependent actions were assessed by comparing effects on normal islets and also following massive toxigenetic β-cell ablation in pIns-MYCERTAM transgenic mice in vivo. Despite over 90% loss of β-cell mass, exendin-4 treatment normalised blood glucose and insulin levels in hyperglycaemic mice, though benefits rapidly waned on withdrawal of treatment. As exendin-4 did not arrest the decline in β-cell mass or turnover in this study, we could directly isolate effects on function of surviving β-cells. Improved glucose homeostasis was associated with dynamic changes in multiple islet genes and pathways in vivo favouring glucose-stimulated insulin secretion, such as Irs2, Pdx1, Sox4, glucokinase, and glycolysis pathway. Several key growth pathways and epigenetic regulators were also differentially expressed. Thus, even in the face of extensive β-cell loss exendin-4 can markedly improve hyperglycaemia by differential gene expression in surviving islet cells.
2014-04-11 | GSE37936 | GEO
Project description:537 million people globally suffer from diabetes. Insulin-producing beta cells are reduced in number in most people with diabetes, but the majority still have some residual beta cells. Disappointingly, none of the many diabetes drugs in common use can increase human beta cell numbers. Recently, small molecules that inhibit the kinase, Dual Tyrosine-Regulated Kinase 1A (DYRK1A), have been shown to induce immunohistochemical markers of human beta cell replication, and this is enhanced by drugs that stimulate the GLP1 receptor (GLP1R) on beta cells. However, it remains to be demonstrated whether these immunohistochemical findings translate into an actual increase in human beta cell numbers in vivo. It is also unknown whether DYRK1A inhibitors together with GLP1R agonists (GLP1RAs) affect human beta cell survival. Here, we demonstrate for the first time that combination of a DYRK1A inhibitor with exendin-4 increases actual human beta cell mass in vivo by 400-700% in diabetic and non-diabetic mice over three months, reverses diabetes in vivo, without significant alteration in human alpha cell mass. The augmentation in human beta cell mass occurs through mechanisms that include enhanced human beta cell proliferation, function, and survival. The increase in human beta cell survival is mediated in part by the islet prohormone, VGF. Taken together, these findings demonstrate the remarkable therapeutic potential and safety profile of the DYRK1A inhibitor-GLP1RA combination for diabetes treatment.
2024-06-28 | GSE249310 | GEO
Project description:GLP-1 analogues, such as exendin-4, preserve functional β-cell mass in various model systems and are revolutionising management of type 2 diabetes. Yet, comparatively little is known about effectiveness in the face of severe β-cell depletion. Moreover, direct and sequential effects of exendin-4 on islet-specific gene expression over time in vivo are not well characterised. To address these issues and others, we have examined the time-dependent effects of exendin-4 treatment on β-cell mass regulation alongside accompanying changes in islet gene expression in vivo. Context-dependent actions were assessed by comparing effects on normal islets and also following massive toxigenetic β-cell ablation in pIns-MYCERTAM transgenic mice in vivo. Despite over 90% loss of β-cell mass, exendin-4 treatment normalised blood glucose and insulin levels in hyperglycaemic mice, though benefits rapidly waned on withdrawal of treatment. As exendin-4 did not arrest the decline in β-cell mass or turnover in this study, we could directly isolate effects on function of surviving β-cells. Improved glucose homeostasis was associated with dynamic changes in multiple islet genes and pathways in vivo favouring glucose-stimulated insulin secretion, such as Irs2, Pdx1, Sox4, glucokinase, and glycolysis pathway. Several key growth pathways and epigenetic regulators were also differentially expressed. Thus, even in the face of extensive β-cell loss exendin-4 can markedly improve hyperglycaemia by differential gene expression in surviving islet cells. Activation of MYCERTAM was achieved through administration of 1mg of 4 hydroxytamoxifen (4OHT; Sigma-Aldrich, St. Louis, MO) by daily intraperitoneal injection. To assess the effect of exendin-4 on MYCER-induced hyperglycaemia, mice were given either twice-daily subcutaneous (sc) injections of exendin-4 (50ug/kg dissolved in 5mls water), or equivalent volumes of water vehicle, starting 2 days prior to 4OHT injections. For microarray analyses parallel mouse experiments were set up using 8-12 week old pIns-MYCERTAM male mice either treated with 4OHT or vehicle (peanut oil) and exendin-4 or vehicle, as described, for 4, 8, 16, 32 and 72 hours (n=3 for each time point and for each of four conditions; 4OHT and exendin-4 treated, peanut oil and exendin-4 treated, 4OHT and water treated, peanut oil and water treated). !Sample_data_processing = After the quality control step, the following 8 samples out of 60 showing poor reproducibility were excluded from our further study: GSM930242, GSM930247, GSM930251, GSM930263, GSM930264, GSM930289, GSM930291, GSM930298.
2014-04-11 | E-GEOD-37936 | biostudies-arrayexpress
Project description:Diabetes mellitus results from an inadequately functioning beta-cell mass. In the adult pancreas, beta-cell mass is dynamic, increasing to meet metabolic demands and decreasing with metabolic or injury insults. Exendin-4 (Ex-4) is a glucagon-like peptide-1 receptor agonist that augments beta-cell mass by increasing beta-cell neogenesis and proliferation and by reducing apoptosis. We utilized a cDNA microarray approach to identify genes that are differentially regulated during islet growth after Ex-4 treatment or a partial pancreatectomy (Ppx). Mice underwent 50% Ppx or sham operation and received Ex-4 or vehicle every 24 hours. cDNA prepared from total pancreatic RNA isolated at 12, 24 and 48 hrs after surgery was hybridized to the PancChip 4.0 microarray.
2005-12-01 | E-CBIL-5 | biostudies-arrayexpress
Project description:Using an unbiased chemical biology approach, we discover harmine as a novel regulator of Treg/Th17 differentiation. Harmine enhances Treg differentiation (working in conjunction with low levels of exogenous TGFb) and inhibits Th17 differentiation. Analysis of global gene expression of Tregs generated using low TGFb + harmine reveals significant similarity to Tregs generated using high TGFb only and suggests relevance of harmine-engaged mechanisms to IBD. Naïve CD4+CD62L+ T cells were purified from Foxp3GFP mice either by MACS or FACS, then cultured in either low TGFb + harmine or high TGFb conditions. GFP+ Tregs were sorted by FACS at day 4.
2015-04-29 | E-GEOD-64247 | biostudies-arrayexpress
Project description:Combination therapy with estrogen and a selective estrogen receptor modulator (SERM) is a promising approach to safely alleviate important side effects related to estrogen deficiency in women at high risk for breast cancer. Data related to endometrial safety of estrogen+SERM co-therapies are limited, however. The primary goal of this study was to evaluate the endometrial profile of low-dose E2 and Tam alone and in combination.
2009-02-03 | GSE14518 | GEO
Project description:The two obstacles that impede a wider application of genetically modified cells expressing therapeutic transgenes for ex vivo gene therapy are the immune mediated rejection of the transplanted cells, combined with their potential to cause iatrogenic oncogenesis. In this study we describe a new cellular vehicle for this form of therapy, termed the cord lining epithelial cell (CLEC). CLECs are derived from the human amnion and incorporate many of the immunoregulatory functions associated with the fetal/maternal interface. We show that CLECs can be safely transfected by phage φC31 integrase to accomplish site-specific integration of a therapeutic human transgene. We also show that transplanted CLECs are not oncogenic in vivo and can be maintained in immunocompetent mice where acute xeno-rejection rapidly destroys other human cell types. Finally, we demonstrate the utility of CLECs for ex vivo gene therapy by delivering human coagulation factor 8 to mice with Hemophilia A. High-resolution copy number profiling was performed on genomic DNA of untreated (GSM315546 and GSM315713) and phage integrase modified CLECs (GSM315974 and GSM316895) using the Human Mapping 500K Array Set (Affymetrix) and the data analyzed using GeneChip Chromosome Copy Number Analysis Tool. Regions of copy number gain or loss were defined as having 3 consecutive SNPs concordant for significant copy number abnormalities. Log2 signal intensity ratios >0.3 and <-0.3 were criteria for significant copy number gain and loss, respectively.
2008-09-01 | E-GEOD-12629 | biostudies-arrayexpress
Project description:Combination therapy with estrogen and a selective estrogen receptor modulator (SERM) is a promising approach to safely alleviate important side effects related to estrogen deficiency in women at high risk for breast cancer. Data related to endometrial safety of estrogen+SERM co-therapies are limited, however. The primary goal of this study was to evaluate the endometrial profile of low-dose E2 and Tam alone and in combination. In this study 16 postmenopausal female cynomolgus macaques were randomized to receive placebo, low-dose micronized estradiol (E2, 0.25 mg/1800 kcal), the SERM tamoxifen (Tam, 20 mg/1800 kcal), or E2+Tam in a parallel-arm design. Endometrial samples were collected after 4 months of treatment and used for microarray analysis.
2010-05-06 | E-GEOD-14518 | biostudies-arrayexpress
Project description:Stromal communication with cancer cells can influence treatment response. We show that stromal and breast cancer (BrCa) cells utilize paracrine and juxtacrine signaling to drive chemotherapy and radiation resistance. Upon heterotypic interaction, exosomes are transferred from stromal to BrCa cells. RNA within exosomes, which are largely non-coding transcripts and transposable elements, stimulates the pattern recognition receptor RIG-I to activate STAT1-dependent anti-viral signaling. In parallel, stromal cells also activate NOTCH3 on BrCa cells. The paracrine anti-viral and juxtacrine NOTCH3 pathways converge as STAT1 facilitates transcriptional responses to NOTCH3 and expands therapy resistant tumor-initiating cells. Primary human and/or mouse BrCa analysis support the role of anti-viral/NOTCH3 pathways in NOTCH signaling and stroma-mediated resistance, which is abrogated by combination therapy with gamma secretase inhibitors. Thus, stromal cells orchestrate an intricate cross-talk with BrCa cells by utilizing exosomes to instigate anti-viral signaling. This expands BrCa subpopulations adept at resisting therapy and re-initiating tumor growth. Breast cancer cells lines and MRC5 fibroblasts were mono-cultured or co-cultured together. Cell types were separated by FACS and gene expression changes were examined using the Affymetrix Human Gene 1.0ST arrays. The effect of tumor-stromal cell interaction on different breast cancer cell types was analyzed using biological replicates. Gene expression changes resulting from knockdown of STAT1 was also investigated.
2014-10-24 | E-GEOD-60995 | biostudies-arrayexpress