Death Receptors as Integrators of Stress-induced inflammation

Información del proyecto

DESTRESS

Identificador del acuerdo de subvención: 101020534

DOI

10.3030/101020534

Fecha de la firma de la CE 13 Agosto 2021

Fecha de inicio 1 Octubre 2021

Fecha de finalización 30 Septiembre 2027

Financiado con arreglo a

• EXCELLENT SCIENCE - European Research Council (ERC)

Coste total

€ 2 499 386,25

Aportación de la UE

€ 2 499 386,25

Coordinado por

THE PROVOST, FELLOWS, FOUNDATION SCHOLARS & THE OTHER MEMBERS OF BOARD, OF THE COLLEGE OF THE HOLY & UNDIVIDED TRINITY OF QUEEN ELIZABETH NEAR DUBLIN
Ireland

Periodic Reporting for period 2 - DESTRESS (Death Receptors as Integrators of Stress-induced inflammation)

Período documentado: 2023-04-01 hasta 2024-09-30

Resumen del contexto y de los objetivos generales del proyecto

Many diseases are associated with chronic long-term inflammation (e.g. cancer, obesity, neurodegeneration, diabetes), which does not have an obvious infectious or acute injury cause, but is an exacerbating factor in these conditions. Instead, these diseases are frequently associated with persistent cell stress that is likely to act as a key driver of inflammation in these settings. However, how inflammation is initiated in response to cell stress remains enigmatic. Here, we will explore the nature of the molecules that sense and promote stress-induced inflammation, which we have dubbed 'SAMPs' (Stress-Associated Molecular Patterns). In particular, we will explore whether members of the TNF family act as integrators of divergent forms of cell stress, leading to inflammation. Understanding how cell stress promotes inflammation would open up a new frontier in inflammation research and would suggest new molecular targets for the treatment of chronic inflammation in multiple disease states.

Trabajo realizado desde el comienzo del proyecto hasta el final del período abarcado por el informe y los principales resultados hasta la fecha

To understand how stress-induced inflammation operates, we have used a number frequently encountered forms of cell stress, including (a) chemotherapeutic drugs that cause DNA damage (e.g. cisplatin, etoposide, doxorubicin and others), (b) chemotherapeutic drugs that trigger protein misfolding (bortezomib, carfilzomib), (c) and ‘BH3 Mimetic’ targeted chemotherapeutic agents that promote mitochondrial stress (Venetoclax, Navitoxlax) and have explored how these widely used drugs promote inflammation. We have discovered that death receptors play a key role in driving inflammation downstream of DNA damage. We have also discovered two novel pathways of inflammation triggered by protein misfolding stress and mitochondrial stress. Furthermore, we have also identified a new way that senescent cells (which are suspected to be a detrimental source of inflammation in tumors) may be eliminated in a therapeutic setting. We are currently exploring how to translate this approach into a therapeutically viable strategy. We have also discovered fundamental connections between the regulation of apoptosis and entry to premature replicative senescence (a cellular state that is often an undesirable outcome of chemotherapy).

Avances que van más allá del estado de la técnica e impacto potencial esperado (incluida la repercusión socioeconómica y las implicaciones sociales más amplias del proyecto hasta la fecha)

We have made important breakthroughs into our understanding of how inflammation is initiated in response to DNA damaging chemotherapeutic drugs. We have also made important breakthroughs in our understanding of how molecular decisions are made between entry into cellular senescence as opposed to undergoing cell death in the context of DNA damaging chemotherapy. The discovery of these molecular decision points suggest new ways of eliminating senescent cells to suppress cancer-associated inflammation. For the next phase of the project, we expect to develop a potential therapeutic, based on protein-degrading technology, targeted towards key regulators of stress-induced inflammation.

Mitochondrial networks in a Senescent tumor cell

Senescent cells stained for mitochondrial proteins