The fellows will become experts on the basic mechanisms of fuel-stimulated insulin secretion, the failure of which is ultimately the cause of Type 2 Diabetes (T2D). Secretion of the hormone is controlled by metabolism of fuels in the beta-cell. Cellular metabolism generates coupling signals, which impact on ion channels and/or the exocytotic machinery in the beta-cell. The current lesson from the genome-wide association studies (GWAS) of T2D is that most identified gene variants associated with the disease are implicated in in beta-cell function. Although these associations are firmly established, the mechanisms whereby they cause disease have remained unresolved. This hampers proper prevention of T2D and development of drugs for “Precision Medicine”.
Specific aim: Understand how gene variants cause beta-cell dysfunction in Type 2 Diabetes Mellitus
The fellows will employ induced pluripotent stem cells (iPSC), as well as cultured clonal rodent and human beta-cells, to examine the impact of genetic variation on relevant functional readouts. The fellow will use genome editing tools (CRISPR/Cas9) complemented by RNA interference (RNAi), all established techniques in the laboratory, to manipulate genes of interest and change risk alleles. The consequences of these manipulations for insulin secretion, beta-cell function and metabolism will be analyzed by an array of biochemical assays and novel imaging tools.
In depth analyses: The fellows will gather data on how gene expression, epigenetic marks, metabolite levels, oxygen consumption and cellular function change when expression and/or the sequence of a T2D candidate gene has been manipulated. For the, analyses, we will use our sequencing facility, metabolomics platform, the Seahorse XF24 flux analyzer of mitochondrial function, as well as real-time in vivo imaging of metabolic and cellular processes, including cellular second messenger systems.
Further details:
Two Postdoctoral Positions ar Lund University