Active Cells, Biochemistry & Physiology Genetics & Molecular Biology

Understanding and manipulating stress signalling: from mechanisms to therapeutics

Funder Wellcome Charity-funded
Recipient organisation MRC Laboratory of Molecular Biology
Funding £3.2M
Period Jan 2025 — Dec 2032

In plain English

AI plain-English summary

Cells under stress—from ageing to infection—activate internal alarm systems that decide whether they repair or die. This lab has discovered a surprising twist: certain drug-like molecules designed to block one stress sensor can instead flip a related sensor into overdrive, a finding that opens a new route to boosting cellular resilience. The problem is that many age-related degenerative diseases, such as motor neuron disease and certain dementias, involve chronic stress signalling that pushes cells toward death. Current treatments cannot correct this. The researchers will now dissect exactly how these molecules activate the stress sensor GCN2, design more selective chemical activators, and test them in disease models with a known genetic link to the integrated stress response. If successful, this work could produce a new class of drugs that enhance a cell’s natural ability to withstand stress, potentially slowing or preventing damage in a range of currently incurable conditions. The project also addresses a fundamental question about how stress-sensing enzymes recognise and modify their targets, with implications for a large family of related enzymes beyond the immediate disease focus.

View original technical description
Numerous stress-signalling pathways are required to ensure cell survival in the face of challenges. My lab aims at identifying strategies that harness these signalling pathways to enhance cellular resilience, a modality generically applicable to improve fitness in diverse diseases, including the age-related degenerative diseases. We recently discovered that potent and optimized ATP-competitive inhibitors of the kinases of the integrated stress response (ISR), PERK and PKR, can paradoxically activate this pathway by directly binding to and activating a sister ISR kinase, GCN2. This proposal aims at developing this exciting finding, of broad relevance. We will dissect the molecular mechanisms of chemical activation of GCN2, identify selective chemical activators of GCN2 and assess their therapeutic potential in diverse disease models, starting with those with a genetic link with the ISR. We will extend the study of ISR kinases activation to reveal the mechanisms by which they recruit their substrate. This research programme will bring fundamental discoveries applicable to a large family of enzymes, with a translational potential relevant to a group of devastating and so far incurable diseases.

View the original record at the funder ↗

Researchers

Anne Bertolotti (EPMC Awardee)

Related Research

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Original classification

Discovery Award

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