Research Interests
Intestinal hormone secretion and action
The intestinal epithelium is scattered with enteroendocrine cells (EECs), which, although only accounting for less than 1% of this tissue, can be considered the biggest endocrine organ in the body. Some of the peptides secreted have important regulatory roles for metabolism; glucagon-like peptide-1 (GLP-1) for example boosts postprandial insulin secretion and is the basis for mimetics with improved plasma half-life now widely used in the treatment of diabetes. GLP-1 and the co-secreted polypeptide YY also reduce food intake, and elevated plasma levels of these hormones correlate with the positive effects of gastric bypass surgery for the treatment of obesity and GLP1R agonists are now well established as weight loss drugs.
Our lab, which works in close collaboration with Fiona Gribble’s group, uses transgenic mice in which cells expressing specific hormones are tagged by fluorescent reporters or Cre-recombinase, allowing identification and/or manipulation of EEC-subsets. We have established intestinal organoids – intestinal epithelial stem cells giving rise to all derived cells including EECs in vitro – from different intestinal sections from these mice and similar organoid cultures derived from human intestinal tissue. We use electrophysiological and live-cell imaging techniques to identify the mechanisms underlying the secretion of GLP-1, glucose-dependent insulinotropic peptide (GIP) and other hormones, with the aim eventually to manipulate their release therapeutically for the treatment of diabetes and obesity. We are developing LC-MS/MS based methods for simultaneous and sensitive detection of gut hormones in biological matrices, which we hope will extend our understanding of integrated EEC-responses to different nutrient challenges and after intestinal surgery. To better understand the targets recruited by these gut hormones we have made mice tagging cells expressing the receptors for some of the secreted peptides, e.g. GLP1R, GIPR and Rxfp4, the receptor for insulin-like peptide-5 (Insl5), which is co-secreted with GLP-1 in the distal colon. Ongoing research focuses on the expression of these receptors in several different nuclei of the central nervous system regulating food intake, preferences and energy homeostasis, using chemogenetic, optogenetic, fibre photometry techniques in combination with behavioural assessment.
Group Members (all joint with Gribble)
Constanza Alcaino, Research Associate - caa62@medschl.cam.ac.uk
Sofia Aleksashina, PhD student - sa2115@medschl.cam.ac.uk
Chris Bannon, Clinical Research Associate - camb3@medschl.cam.ac.uk
Sijing Cheng, Research Associate - sc2470@medschl.cam.ac.uk
Adam Davison, Research Associate - ad2256@cam.ac.uk
Gabriela Gil, Research Assistant - gg550@cam.ac.uk
Htar Htar Hlaing, Clinical Research Associate - hhh32@cam.ac.uk
Paula-Peace James-Okoro, PhD student - ppoj2@medschl.cam.ac.uk
Richard Kay, Senior Research Associate - rgk27@medschl.cam.ac.uk
Jo Lewis, Research Associate - jl2033@medschl.cam.ac.uk
Tianyi Lu, MPhil student - tl602@cam.ac.uk
Mireia Montana - mm2727@medschl.cam.ac.uk
Danae Nuzzaci, Research Associate - dn371@medschl.cam.ac.uk
Austin Punnoose, Research Assistant in the Mass Spectrometry Core - Avp34@medschl.cam.ac.uk
Marta Santos Hernandez, Visiting Post-doctoral Fellow - ms2896@medschl.cam.ac.uk
Christopher Smith, Research Associate - cas228@medschl.cam.ac.uk
Mae Tabbada, PhD student - jmt97@cam.ac.uk
Nademah Tamkin - nr535@medschl.cam.ac.uk
Research Funding
Medical Research Council (MRC)
Biotechnology and Biological Sciences Research Council (BBSRC)
National Institute for Health Research – Biomedical Research Centre (NIHR-BRC)
