Completed Genetics & Molecular Biology Digestion, Kidneys & Other Organs

The role of the transfer RNA repertoire in generating secretory phenotypes during epithelial homeostasis

Funder MRC (part of UKRI)
Recipient organisation University of Glasgow
Funding £1.4M
Period Jul 2017 — Jul 2023

In plain English

AI plain-English summary

Every 3 to 5 days, the human gut completely replaces its lining, forcing millions of cells to switch from rapid growth to mass-producing digestive secretions. This project asks how the cell’s protein-making machinery handles that abrupt change in workload. The problem is that scientists understand how stem cells divide and how mature cells secrete, but they know almost nothing about the transition between the two. As a gut cell leaves the stem-cell niche in the intestinal crypt, it must stop making proteins for growth and start making proteins for secretion—a fundamental shift in its molecular job description. This project will track exactly how the cell’s transfer RNA repertoire and ribosome composition adapt to that change, then test the consequences by engineering mice with altered protein-synthesis machinery. This is fundamental science. It will not produce a drug or a diagnostic next year. But the gut’s ability to renew itself while maintaining a barrier against microbes and digesting food is a feat of tissue engineering that no synthetic system can match. Understanding how a complex tissue structures itself—how it allocates protein production to different cell types at different times—could eventually inform therapies for inflammatory bowel disease, intestinal damage from chemotherapy, or conditions where the gut barrier fails. Similar work on protein synthesis in other systems has already revealed how cells fine-tune their output in response to stress, opening unexpected avenues for treating cancer and neurodegeneration.

View original technical description
Organs such as the intestine need to constantly renew their cells in order to maintain integrity. To do this, the intestine has a small population of stem cells which keep growing and dividing to provide a supply of new cells to support gut function. These stem cells are situated in a special niche in the crypts of the gut, and the supply of cells that they produce move out of the crypt and into other parts of the intestinal membrane. Upon leaving the crypt, gut cells stop dividing and start to perform other important functions, such as the production of secretions that assist digestion. All cells make proteins, and the catalogue of proteins that they make varies according to their function. Thus the population of gut stem cells that are rapidly proliferating must make proteins to support cell growth and division. However, when gut cells leave the crypt and stop growing, they cease to make proteins for cell growth and turn their hand to large-scale production of secretions. The cell's protein synthesis machinery must adapt to this major change in the menu of proteins it produces. This project will investigate the alterations to the protein synthesis machinery that occur as cells leave the stem cell niche in the intestinal crypt, stop dividing and start to make secreted proteins in large quantities. We will then make genetically-modified mice with altered protein synthesis machinery to determine how this influences the secretory function and integrity of the intestine. These genetically modified mice and the information that we gain from them will enable us to determine how a complex tissue like the gut is able to structure itself, and how it perform functions such as nutrient adsorption and the maintenance of the gut microbiota.

View the original record at the funder ↗

Researchers

Jim Norman (Principal Investigator)Martin Bushell (Co-Investigator)

Related Research

Grants with similar aims, by meaning.

Homeostasis of Glial Cells in the Mammalian Gut
Stem Cell Derived Signals in Intestinal Stem Cell Homeostasis
Role of chromatin dynamics in regulation of intestinal innate immunity gene expression
Local and systemic functions of the intestine in health and disease.
Epigenetic modulation of WNT signalling in the ageing human intestinal epithelium: consequences for tissue homeostasis

Original classification

Research Grant

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