Deciphering the Mechanism and Roles of Muscarinic and Purinergic Calcium Signals in the Human Colonic Epithelium

Lee, Alvin (2021) Deciphering the Mechanism and Roles of Muscarinic and Purinergic Calcium Signals in the Human Colonic Epithelium. Doctoral thesis, University of East Anglia.

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Abstract

The human large intestine is lined by a monolayer of polarized epithelial cells, which form invaginations known as ‘Crypts of Lieberkühn’ and serves as a barrier between the gut luminal contents and the systemic circulation. In order to maintain this barrier, the epithelium constantly renews and replenishes itself, a process known as tissue homeostasis. This process is driven by multipotent intestinal stem cells residing at the base of crypts which give rise to specialised epithelial cells. Loss of tissue homeostasis is associated with an increased risk of major intestinal diseases, such as colorectal cancer.
Stem cell-driven tissue renewal is regulated by luminal and systemic factors. Luminal-sensing of gut contents – nutrients, microbes, and their metabolites – triggers the release of hormones, cytokines and chemokines from the epithelium and gut immune cells. Higher levels of control that modulate the epithelium and integrate luminal inputs are exerted at the basal pole by neurotransmitters, such as acetylcholine and ATP. These neurotransmitters affect gut immunity and motility, mucus and fluid and electrolyte secretion, proliferation, and cancer development.
This thesis is interested in expanding our understanding of how the colonic epithelium integrates signalling inputs. Calcium is a signal integrator that regulates gut homeostasis. In drosophila, external signalling molecules causes calcium oscillations which influences intestinal stem cells. In mouse, carbachol – a non-hydrolysable analogue of acetylcholine – increases cytosolic calcium concentrations and modulates bicarbonate secretion. Calcium signalling also has a complex role on the development and progression of cancer. However, the spatial-temporal status of calcium signals in primary human intestinal epithelium remains unclear.
This thesis elucidates components of the calcium signalling toolkit and investigates the spatial-temporal status of calcium signals in cultured human intestinal crypts and organoids. It also explores the physiological roles of calcium signalling in maintaining gut tissue homeostasis and investigates the status of calcium signalling in colorectal cancer.

Item Type:	Thesis (Doctoral)
Faculty \ School:	Faculty of Science > School of Biological Sciences
Depositing User:	Nicola Veasy
Date Deposited:	06 Apr 2022 11:48
Last Modified:	06 Apr 2022 11:48
URI:	https://ueaeprints.uea.ac.uk/id/eprint/84498
DOI:

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