Gene expression of glucose homeostasis in a pancreas-liver microphysiological system
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1048431 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27051029_1.fastq.gz | Fastqsanger.gz | |||
| SRR27051029_2.fastq.gz | Fastqsanger.gz | |||
| SRR27051030_1.fastq.gz | Fastqsanger.gz | |||
| SRR27051030_2.fastq.gz | Fastqsanger.gz | |||
| SRR27051031_1.fastq.gz | Fastqsanger.gz |
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Project description:Current research on metabolic disorders and diabetes relies on animal models because multi-organ diseases cannot be well studied with the standard in vitro assays. Here, we connect models of key metabolic organs, pancreas and liver, on a microfluidic chip to enable diabetes research in a human-based preclinical system. Aided by mechanistic mathematical modelling, we show that hyperglycemia and high cortisone induce glucose dysregulation in the pancreas-liver microphysiological system (MPS) mimicking a diabetic phenotype seen in patients with glucocorticoid-induced diabetes. In this diseased condition, pancreas-liver MPS displays beta-cell dysfunction, steatosis, elevated ketone-body secretion, increased glycogen storage, and upregulated gluconeogenic gene expression. In turn, a physiological culture condition rescues the glucose tolerance and beta cell function. This method was evaluated for repeatability in two laboratories and was effective in multiple pancreatic islet donors. The model also provides a platform to identify new therapeutic targets as demonstrated with a combined transcriptome and proteome analysis.
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Project description:Current research on metabolic disorders and diabetes relies on animal models because multi-organ diseases cannot be well studied with the standard in vitro assays. Here, we connect models of key metabolic organs, pancreas and liver, on a microfluidic chip to enable diabetes research in a human-based in vitro system. Aided by mechanistic mathematical modelling, we show that hyperglycemia and high cortisone induce glucose dysregulation in the pancreas-liver microphysiological system (MPS) mimicking a diabetic phenotype seen in patients with glucocorticoid-induced diabetes. In this diseased condition, pancreas-liver MPS displays beta-cell dysfunction, steatosis, elevated ketone-body secretion, increased glycogen storage, and upregulated gluconeogenic gene expression. In turn, a physiological culture condition maintains the glucose tolerance and beta cell function. This method was evaluated for reproducibility in two laboratories and was effective in multiple pancreatic islet donors. The model also provides a platform to identify new therapeutic proteins as demonstrated with a combined transcriptome and proteome analysis.
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Project description:Maintenance of normal glucose homeostasis is disturbed in diabetes. In the β cell, this involves a glucose sensor converting increased glucose levels to insulin secretion. Understanding the developmental regulatory networks that define a fully functional β cell is important for elucidating the genetic origins of the disease and deriving mature β cells for therapy. Here we show that Aldh1b1 regulates the timing of differentiation in the developing pancreas and the patterning of β cells. In its absence, expression of key β cell transcription factors is deregulated at birth. Null animals become glucose intolerant and hyperglycemic with age. Beta cell dysfunction is associated with extensive transcripteome changes, increased oxidative stress, energy depletion and defects in both glucose sensing and stimulus coupling secretion. These findings identify Aldh1b1 as a central regulator of the transition from the pancreas endocrine progenitor to the committed β cell and demonstrate that changes in the timing of this transition manifest much later in adult life with β cell dysfunction. Islets were isolated from postnatal day one and 8 week old Aldh1b1 null and wt mice. For each P1 samples islets from three mice were combined. Each week 8 sample came from a single mouse. Three samples were analysed per genotype and time point
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Project description:The pancreas plays a critical role in maintaining glucose homeostasis through the secretion of hormones from the islets of Langerhans. Glucose-stimulated insulin secretion (GSIS) by the pancreatic beta-cell is the main mechanism for reducing elevated plasma glucose.
Here we present a systematic modeling workflow for the development of kinetic pathway models using the Systems Biology Markup Language (SBML). An important factor was the reproducibility and exchangeability of the model, which allowed the use of various existing tools.
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Project description:to compare the incremental advances that each cell type brings to the phenotype of the others in the glomerulus we compared TGCs (triculture), BGCs (co-culture), and plate cultures (monocultures) The function of the glomerulus depends on complex cell-cell/matrix interactions and replication of this in vitro would aid biological understanding in both health and disease. Previous models have not fully reflected all cell types and interactions present. We report here the development of a microphysiological system which contains all resident renal cell types in an anatomically relevant manner. We demonstrate functionally appropriate retention of albumin in the system along with providing a detailed transcriptomic analysis of the contributing biology of each cell type. The important role of mesangial cells is shown in promoting the health and maturity of the other cell types. AdditionallyAdditionally, we demonstrate that glomerular cells in simple 2D culture exhibit a state more reflective of human disease than previously recognised. This in vitro model will expand our capability to investigate glomerular biology in a more translatable manner by the inclusion of the important mesangial cell compartment.
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