Development of multipotent cells in human embryonic pancreas and the influence of GLP-1
Lead Research Organisation:
University of Manchester
Department Name: Medical and Human Sciences
Abstract
Diabetes mellitus (DM) is a disease that affects at least 1.2 million people in the UK. It can lead to a number of complications, including blindness and kidney disease. Although injectable insulin represents a life-saving treatment for Type 1 diabetes, it falls a long way short of a cure. Restoring the cells in the pancreas that are damaged in diabetes (beta cells) could offer a potential cure. However to do this in a safe manner a greater understanding of how beta cells first occur during early human development is required. My research will aim to address this, by studying how pancreatic cells develop, identifying the genes and signalling processes involved. Recently I have begun to tease apart the time frame when early pancreatic cells are capable of forming all cells in the pancreas. In addition, preliminary evidence suggests a hormone, glucagon-like peptide 1 (GLP-1) is important. Significantly, drugs that mimic GLP-1 are currently being used in the treatment of Type 2 DM. Any information on how these agents might stimulate new beta cell formation would therefore be very exciting. Better understanding of underlying mechanisms might also bring to light new pathways that could be exploited therapeutically for beta cell regeneration.
Technical Summary
The objective of my research is to define how differentiation of the different cell lineages occurs from multipotent progenitors in the developing human pancreas. I will also define how glucagon-like peptide 1 (GLP-1) signals in these multipotent cells to favour endocrine differentiation.
My specific aims are for a three-year programme of research:
1. To define multipotent progenitors within early human pancreas and their preference for future endocrine or exocrine differentiation by studying expression of the transcription factors SOX9, PDX1, FOXA2, NKX6.1, NGN3, PTF1A, LRH1 and GATA4
2. To define the GLP-1 signalling axis that is apparent within the early human embryo
3. To determine how GLP-1 affects the multipotent pancreatic progenitors and their differentiation
Design & methodology: these studies will utilise a highly distinctive collection of human embryonic and fetal material from the first trimester of pregnancy and employ immunohistochemistry, explant culture, hormone assay, realtime PCR and molecular analyses of promoter and enhancer activity (e.g. transient transfection, luciferase assays, EMSAs and ChIP)
Potential scientific & medical outcome, and anticipated patient benefits: Regenerative cell therapy restoring insulin-secreting pancreatic beta cells is of great interest in treating diabetes (both type 1 and type 2). It is vitally important that we understand how to do this safely and in a physiologically normal manner. In this regard, the development of beta cells as it first occurs during early human development has been viewed as the gold standard; yet datasets on how this occurs, especially in human, are incomplete. At what stage the human pancreas contains truly multipotent progenitors (capable of forming exocrine, ductal and endocrine lineages) has never been accurately defined yet there is emerging data from mouse that this period is malleable. In addition, I have some preliminary data which suggests that glucagon-like peptide 1 (GLP-1) signalling is important. This is very exciting as GLP-1 analogues are in licensed clinical use for type 2 diabetes. Thus, any information on how these agents might stimulate new beta cell formation would be very exciting. Better understanding of underlying mechanisms might also bring to light new pathways that could be exploited therapeutically for beta cell regeneration.
My specific aims are for a three-year programme of research:
1. To define multipotent progenitors within early human pancreas and their preference for future endocrine or exocrine differentiation by studying expression of the transcription factors SOX9, PDX1, FOXA2, NKX6.1, NGN3, PTF1A, LRH1 and GATA4
2. To define the GLP-1 signalling axis that is apparent within the early human embryo
3. To determine how GLP-1 affects the multipotent pancreatic progenitors and their differentiation
Design & methodology: these studies will utilise a highly distinctive collection of human embryonic and fetal material from the first trimester of pregnancy and employ immunohistochemistry, explant culture, hormone assay, realtime PCR and molecular analyses of promoter and enhancer activity (e.g. transient transfection, luciferase assays, EMSAs and ChIP)
Potential scientific & medical outcome, and anticipated patient benefits: Regenerative cell therapy restoring insulin-secreting pancreatic beta cells is of great interest in treating diabetes (both type 1 and type 2). It is vitally important that we understand how to do this safely and in a physiologically normal manner. In this regard, the development of beta cells as it first occurs during early human development has been viewed as the gold standard; yet datasets on how this occurs, especially in human, are incomplete. At what stage the human pancreas contains truly multipotent progenitors (capable of forming exocrine, ductal and endocrine lineages) has never been accurately defined yet there is emerging data from mouse that this period is malleable. In addition, I have some preliminary data which suggests that glucagon-like peptide 1 (GLP-1) signalling is important. This is very exciting as GLP-1 analogues are in licensed clinical use for type 2 diabetes. Thus, any information on how these agents might stimulate new beta cell formation would be very exciting. Better understanding of underlying mechanisms might also bring to light new pathways that could be exploited therapeutically for beta cell regeneration.