About the Project
T1D is an autoimmune disorder of the endocrine pancreas, caused by destruction of insulin-producing β-cells resulting to insulin deficiency thus, causing dysregulation of glucose. The main line of treatment for T1D requires the administration of insulin however, a sub-population of patients are not fully compliant with an exogenous source of insulin and suffer from hypoglycaemia unawareness, whereby patients fail to sense a significant fall in blood glucose below normal levels, which can cause neurogenic symptoms and in severe cases, cause comas.
A strategy for restoring endogenous insulin production involves pancreatic islet transplantation therapy, which utilises pancreatic tissue from donors to isolate pancreatic islet cells, which are subsequently transplanted into patients. The Edmonton protocol is commonly employed to infuse islets from a cadaveric donor pancreas into the patient’s portal vein.1 Immunosuppressant drugs are used to circumvent autoimmune destruction of transplanted islets. Islet transplantation therapy with immunosuppressance has shown promising clinical outcomes, where patients are independent from exogenous insulin for >5 years with significant improved glycaemic control and reduced complications such as neuropathy, retinopathy and nephropathy.2,3
Studies to circumvent the use of pancreatic donor tissue has excelled pioneering work to derive insulin-producing β-cells, from the definitive endoderm (DE) and pancreatic progenitors in vitro.2-5 The generation of functional human pancreatic β-cells in vitro, which responds to glucose and co-express additional hormones such as glucagon, a marker for endocrine α-cell expression, has proved successful. One method to produce functional pancreatic β-cells from stem cells involves the use of multiple reagents and steps to control the differentiation of pluripotent stem cells into pancreatic β-cells. Therefore, such methods are not applicable to biotechnological production or scale-up.
We have recently developed a panel of chemical tools to show, for the first time, the efficient directed differentiation of pancreatic embryonic tissue to endocrine tissue with an increased expression of insulin-producing β-cells. Our protocol could be applied for the generation of pancreatic Islets with enhanced β-cell/insulin expression in vitro and circumvent the use of donor pancreatic tissue.
The successful candidate will now create compounds with drug-like/biocompatible features that will be assessed to differentiate human embryonic stem-derived pancreatic progenitor cells to functional, insulin-producing pancreatic β-cells. The successful candidate will have access to state-of-the-art molecular modelling packages to design compounds, and work in newly refurbished laboratories to synthesise target compounds and assess compound inhibitory activity at the enzymatic level. The successful candidate will have opportunities to visit laboratories at the University of Bath and present their research at conferences nationally and internationally.
It is estimated that over 5 million people will have diabetes by 2025, which will be the equivalent of 400 cases daily (17 cases per hour). Approximately 850 thousand people currently have undiagnosed type-2 diabetes and are at risk of becoming insulin dependent. Many people (~240 thousand) with undiagnosed diabetes may have a lower life expectancy.
It has been estimated that 10 billion pounds a year (10%) of the NHS budget is spent on treating diabetes or complications arising from diabetes.
Therefore, new strategies to combat insulin-resistance and insulin insensitivity could be of great value to patient lives and the NHS.
2) D’Amour, K.A. et al. Production of pancreatic hormone-expressing endocrine cells from human embryonic stem cells. Nat. Biotechnol. 24, 1392–1401 (2006).
3) Rezania, A. et al. Maturation of human embryonic stem cell-derived pancreatic progenitors into functional islets capable of treating pre-existing diabetes in mice. Diabetes, 61, 2016–2029 (2012).
4) Kroon, E. et al. Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo. Nat. Biotechnol. 26, 443–452 (2008).
5) D’Amour, K.A. et al. Efficient differentiation of human embryonic stem cells to definitive endoderm. Nat. Biotechnol. 23, 1534–1541 (2005).
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