Investigating the activation of IRE-1 as a novel regulator of ageing

To survive, organisms must respond to stress in a way that maintains internal homeostasis. However, this ability to maintain homeostasis is lost with age, leading to fragility and disease. Within cells, maintenance of homeostasis is orchestrated by cellular stress responses.

A key stress response that plays important roles in health and disease is the unfolded protein response (UPR), which detects stress in the endoplasmic reticulum and activates molecular mechanisms to restore equilibrium. The ability to activate the UPR declines with age, but the Taylor lab has found that restoring the UPR in the tractable nematode worm C. elegans can substantially increase lifespan.

This work has also revealed a novel route to activating the UPR, triggered by signals from neurons, which leads to improved health and resilience across the animal.

However, we still don't know how this neuronal signalling mechanism activates the key UPR regulator IRE-1 in downstream cells. Understanding this novel mode of IRE-1 activation is key to utilising this pathway to develop treatments for age-associated diseases. We therefore aim to learn which molecules are required in downstream cells to activate IRE-1 in response to neuronal signals.

This project will achieve that using genetic and cell biological approaches in C. elegans, with the following objectives:

1. Identification of genes required in the intestine of C. elegans for UPR activation via neuronal signals, using tissue-specific RNAi screening.

2. Determining the role of a candidate pathway known to be involved in UPR activation in human cancer cells, using CRISPR mutagenesis and overexpression.

3. Investigating the roles of changes in intracellular calcium and ER redox status, using intestinal Ca2+ sensors and ER redox sensors.

Finally, we will explore the conservation of the identified mechanism(s) in human intestinal organoids, through a collaboration with Dr. Mark Williams at UEA.