Summary
My group aims at fostering the regeneration of insulin-producing β-cells in the diabetic pancreas by promoting the reprogramming of other islet endocrine “non-β” cells. I will use mice and human islets to trigger the metabolic reprogramming of: i) peripheral organs, in order to reduce hyperglycemia, and ii) human islet non-β-cells, to induce their acquisition of insulin secretion.
I developed transgenics to elicit total (>99%) or graded (5-90%) β-cell loss. These mice revealed that non-β-cells, which produce other hormones, can naturally switch to insulin production upon β-cell loss, and lead to diabetes recovery. My group recently showed that human non-β-cells, from healthy or diabetic donors, also display plasticity and can engage in regulated insulin secretion.
What metabolic adaptations occur in peripheral organs in response to insulin deficiency, but without complications? Can metabolic reprogramming of peripheral organs, based on these adaptations, suffice to control glycemia? Can metabolic reprogramming change the identity of a cell?
Natural recovery of euglycemia after β-cell loss is documented in mice. To know the mechanisms driving relief, my lab will characterize islet cell dynamics and circulating molecules (metabolites, RNA, peptides) after various degrees of β-cell loss. We will perform a full analysis of blood and peripheral organs in recovered mice, and an array of genetic and pharmacological experiments modulating BAT mass and function to test its role in taming hyperglycemia.
We will explore and define the metabolic differences between human β- and non-β-cells. Using monotypic “pseudoislets” we will do RNAseq, proteomics and metabolomics after exposure to glucose. We will quantify oxygen consumption, extracellular acidification and ATP production in response to nutrients and metabolic toxins. From this, we will genetically (CRIPR-Cas9) and chemically reprogram the metabolism of human non-β-cells to boost the expression of β-like genes.
I developed transgenics to elicit total (>99%) or graded (5-90%) β-cell loss. These mice revealed that non-β-cells, which produce other hormones, can naturally switch to insulin production upon β-cell loss, and lead to diabetes recovery. My group recently showed that human non-β-cells, from healthy or diabetic donors, also display plasticity and can engage in regulated insulin secretion.
What metabolic adaptations occur in peripheral organs in response to insulin deficiency, but without complications? Can metabolic reprogramming of peripheral organs, based on these adaptations, suffice to control glycemia? Can metabolic reprogramming change the identity of a cell?
Natural recovery of euglycemia after β-cell loss is documented in mice. To know the mechanisms driving relief, my lab will characterize islet cell dynamics and circulating molecules (metabolites, RNA, peptides) after various degrees of β-cell loss. We will perform a full analysis of blood and peripheral organs in recovered mice, and an array of genetic and pharmacological experiments modulating BAT mass and function to test its role in taming hyperglycemia.
We will explore and define the metabolic differences between human β- and non-β-cells. Using monotypic “pseudoislets” we will do RNAseq, proteomics and metabolomics after exposure to glucose. We will quantify oxygen consumption, extracellular acidification and ATP production in response to nutrients and metabolic toxins. From this, we will genetically (CRIPR-Cas9) and chemically reprogram the metabolism of human non-β-cells to boost the expression of β-like genes.
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More information & hyperlinks
| Web resources: | https://cordis.europa.eu/project/id/884449 |
| Start date: | 01-09-2020 |
| End date: | 31-08-2025 |
| Total budget - Public funding: | 2 499 337,50 Euro - 2 499 337,00 Euro |
Cordis data
Original description
My group aims at fostering the regeneration of insulin-producing β-cells in the diabetic pancreas by promoting the reprogramming of other islet endocrine “non-β” cells. I will use mice and human islets to trigger the metabolic reprogramming of: i) peripheral organs, in order to reduce hyperglycemia, and ii) human islet non-β-cells, to induce their acquisition of insulin secretion.I developed transgenics to elicit total (>99%) or graded (5-90%) β-cell loss. These mice revealed that non-β-cells, which produce other hormones, can naturally switch to insulin production upon β-cell loss, and lead to diabetes recovery. My group recently showed that human non-β-cells, from healthy or diabetic donors, also display plasticity and can engage in regulated insulin secretion.
What metabolic adaptations occur in peripheral organs in response to insulin deficiency, but without complications? Can metabolic reprogramming of peripheral organs, based on these adaptations, suffice to control glycemia? Can metabolic reprogramming change the identity of a cell?
Natural recovery of euglycemia after β-cell loss is documented in mice. To know the mechanisms driving relief, my lab will characterize islet cell dynamics and circulating molecules (metabolites, RNA, peptides) after various degrees of β-cell loss. We will perform a full analysis of blood and peripheral organs in recovered mice, and an array of genetic and pharmacological experiments modulating BAT mass and function to test its role in taming hyperglycemia.
We will explore and define the metabolic differences between human β- and non-β-cells. Using monotypic “pseudoislets” we will do RNAseq, proteomics and metabolomics after exposure to glucose. We will quantify oxygen consumption, extracellular acidification and ATP production in response to nutrients and metabolic toxins. From this, we will genetically (CRIPR-Cas9) and chemically reprogram the metabolism of human non-β-cells to boost the expression of β-like genes.
Status
SIGNEDCall topic
ERC-2019-ADGUpdate Date
27-04-2024
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