Expression of metabolic hormone signalling genes in the brain of a triprolyl-human amylin transgenic mouse model of type 2 diabetes
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PROVIDER: PRJNA549501 | ENA |
REPOSITORIES: ENA
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Project description:There is a need for greater understanding of the molecular mechanism underlying the development of insulin resistance in type 2 diabetes, and new models in which to study this. The hormone amylin is postulated to be involved in the development of this disease, as human amylin (hA) forms amyloid in the pancreases of diabetic patients, and wild-type hA oligomers have been shown to be cytotoxic to β-cells. By contrast, rodent amylin is non-amyloidogenic, so mice expressing wild-type hA have been developed. However, amylin-evoked β-cell loss in these models limits the secretion of amylin and insulin. We have developed transgenic mice that overexpress [25, 28, 29triprolyl]human amylin, a non-amyloidogenic variant of amylin, designated the Line 44 (L44) model. These mice develop obesity and hyperglycaemia. We examined the expression of 43 genes involved in amylin, insulin and leptin signalling in the brain of this model, at different disease stages, using the NanoString nCounter (NanoString Technologies, Seattle, WA, USA). After onset of diabetes, mice remained hyperglycaemic for a period of time but blood glucose levels eventually returned to normoglycaemia. The incidence of diabetes (defined as having blood glucose measurements > 11 mM over 3 consecutive weeks) was gene-dose dependent; 81% of homozygous mice and 59% of hemizygous mice developed diabetes over 400 days. A proportion of nontransgenic mice (33%) also developed diabetes. As these were bred from hemizygous pairs this may be the result of epigenetic or environmental factors.
2019-10-10 | GSE132940 | GEO
Project description:As transgenic INSC94Y-pigs develop a stable diabetic phenotype we were able to study the influence of elevated blood glucose levels on primary immune cells in vivo. We investigated the neutrophil proteome and compared data of transgenic animals to a control group. A total of 2371 proteins describing the whole neutrophil proteome were identified, including 396 proteins (17% of proteome) newly associated to expression in porcine neutrophils. Our studies provide novel information on the porcine granulocyte proteome and contribute to a better understanding of molecular mechanisms involved in altered immune cell function in diabetes. The data presented here is highly relevant for veterinary medicine and has translational quality for diabetes in human.
2020-06-04 | PXD017274 | Pride
Project description:WRKY genes are transcription factors involved in plant response to pathogen attacks in many plant species. These proteins have been shown to activate expression of defence genes in a salicylic acid- and/or jasmonic acid-dependent signalling pathway. To understand the molecular mechanisms involved in grapevine defence, we previously identified a WRKY gene, VvWRKY1, which was able to enhance tolerance to fungal pathogens when overexpressed in tobacco. To elucidate its role in grapevine, we generated transgenic grapevines that overexpress VvWRKY1. Microarray analyses were performed to compare global gene expression in leaves of the transgenic and wild-type lines. Results showed that expression of genes encoding defence-related proteins was enhanced in the transgenic 35S::VvWRKY1 line. Quantitative RT-PCR analysis confirmed that three genes putatively involved in jasmonic acid signalling pathway, two genes encoding JASMONATE ZIM-domain (JAZ) proteins and one lipoxygenase, are over-expressed. The ability of VvWRKY1 to trans-activate their corresponding promoters was confirmed by transient expression assay in grape protoplasts. After challenging with the downy mildew pathogen Plasmopara viticola, resistance was enhanced in the transgenic line compared to the wild-type line. These results suggest that VvWRKY1 transcription factor is able to control plant disease resistance to one of the main grapevine pathogen by activating jasmonic acid signalling pathway in grapevine.
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Project description:INSC94Y transgenic pigs serve as a valuable model for permanent neonatal diabetes mellitus. Through genetically engineered modifications in the insulin (INS) gene, this model presents with impaired insulin secretion, resulting elevated fasting blood-glucose levels (hyperglycemia) [1].One of the severe complications of diabetes mellitus are hypoglycemia-mediated morphological abnormalities in the retina, also described as diabetic retinopathy (DR). Adjacent to the retina lies the vitreous, a gelatinous, highly hydrated matrix, which is important for ocular function and retinal physiology. It contains variety of proteins and signaling molecules, which are useful for the characterization of the biological activity of the vitreous itself, and may help to elucidate molecular processes occurring in the retina, especially under pathophysiological conditions and in disease. To gain insight into the proteomic profile of porcine vitreous and detect possible differences relevant to DR pathogenesis, we used discovery proteomics for analysis of INSC94Y vitreous compared to wild-type controls. Reference: [1] Renner, S.; Braun-Reichhart, C.; Blutke, A.; Herbach, N.; Emrich, D.; Streckel, E.; Wunsch, A.; Kessler, B.; Kurome, M.; Bahr, A.; et al. Permanent neonatal diabetes in INS(C94Y) transgenic pigs. Diabetes 2013, 62, 1505-1511, doi:10.2337/db12-1065.
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Project description:The wheat gene Lr1 imparts resistance to certain races of the leaf rust pathogen Puccinia triticina. However, the biological basis underlying the complex resistance mechanisms remains largely unknown. Gene expression profiling analyses using the Affymetrix GeneChipM-BM-. Wheat Genome Array were performed with six independent Lr1 transgenic lines sampled before inoculation (0h) and at 6 and 24 h after inoculation with the avirulent P. triticina race CCDS. For the 6 and 24 h time points, 3M-BM- 384 probe sets corresponding to 2M-BM- 978 transcripts were differentially expressed as compared to the plants before inoculation. Genes involved in defence signalling were triggered as early as 6 h post inoculation (HPI) and included COI1, the primary component of jasmonic acid signalling. By 24 HPI, a shift in plant cellular metabolism, namely carbon conservation, was notable. The enzymes of glycolysis and gluconeogenesis were down-regulated, however, enzymes linked to alternative carbon sequestration processes such as the glyoxylate cycle were up-regulated. Also at 24 HPI, various secondary signalling molecules belonging to the various hormone signalling pathways were triggered. These microarray data suggest that the Lr1 mediated leaf rust resistance is achieved by early onset of defence signalling followed by co-ordinated interplay of metabolism alteration and elicitation of defence responses. We used microarrays to detail the early gene expression events underlying Lr1-mediated resistance to Puccinia triticina pathogen in wheat. Three biological replicates with six independent Lr1 transgenic lines were used in this study to eliminate the possibility of false discovery of genes due to copy number variation or the position of insertion of the transgene Lr1. Early time points of 6 and 24 HPI were compared to 0 h (prior to inoculation) to capture the early signalling events involved in Lr1-mediated response to rust infection.
2012-09-14 | E-GEOD-32151 | biostudies-arrayexpress
Project description:Insulin-like growth factor (IGF1R) signalling has been implicated to play an important role in regulation of cardiac growth, hypertrophy and contractile function, and has been linked to the development of age related congestive heart failure. Here we address the question to what extent cardiomyocyte specific IGF1 signalling is essential for maintenance of the structural and functional integrity of the adult murine heart. To investigate the effects of IGF1 signalling in the adult heart without confounding effects due to IGF1 over-expression or adaptation during embryonic and early post-natal development, we inactivated the IGF1R by a 4-hydroxy tamoxifen inducible Cre recombinase in adult cardiac myocytes. Efficient inactivation of the IGF1R (iCMIGF1RKO) as assessed by Western analysis and real-time PCR went along with reduced IGF1-dependent AKT and GSK3β-phosphorylation. Functional analysis by conductance manometry and magnetic resonance imaging (MRI) revealed no functional alterations in young adult iCMIGF1RKO mice (age 3 month). However, when induced in aged mice (11 month) diastolic cardiac function was depressed. To address the question if insulin signalling might compensate for the defective IGF1R signalling we inactivated β-cells by streptozotocin. However, the diabetes associated functional depression was similar in controls and iCMIGF1RKO mice. Similarly, analysis of the cardiac gene expression profile on 44K microarrays did not reveal activation of overt adaptive processes. Endogenous IGF1 receptor signalling is required for conservation of cardiac function of the aging heart, but not for the integrity of cardiac structure and function of young hearts. Four samples of each group: the control group, positive for Cre recombinase, but negative for the floxed IGF-1R and the experimental group with double transgenic mice (merCremer/+ IGFloxP/IGFloxP).
2012-07-31 | E-GEOD-32936 | biostudies-arrayexpress
Project description:Insulin and insulin-like growth factor signalling regulates a broad spectrum of growth and metabolic responses to a variety of internal and environmental stimuli. Such responses can be tailored so that changes in insulin signalling result in distinct physiological responses to different stimuli. For example, the inhibition of insulin-like signalling is key in the responses of the nematode C. elegans to both osmotic stress and starvation, but these two stresses result in responses that are both physiologically and molecularly distinct. How does reduced insulin-like signalling elicit different responses to different environmental stimuli? We report that neurohormonal signalling involving the C. elegans cytosolic sulfotransferase SSU-1 controls developmental arrest in response to osmotic stress but does not control the distinct developmental arrest that occurs in response to starvation. SSU-1 functions in a single pair of sensory neurons to control intercellular signalling -- likely by catalyzing the synthesis of a steroid hormone -- via the nuclear hormone receptor NHR-1. SSU-1-controlled signalling antagonizes insulin-like signalling and hence modulates insulin sensitivity. In short, we describe a previously unknown neurohormonal signalling pathway that is required specifically for some but not all consequences of reduced insulin-like signalling. In mammals, the nervous system plays a similarly important yet poorly understood role in modulating insulin sensitivity. Our results suggest that the mammalian nervous system might regulate insulin sensitivity via sulfotransferase-controlled neurohormonal signalling.
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