Descripción del proyecto
Un horizonte nuevo para la investigación sobre la inflamación
La inflamación es una reacción de defensa del organismo causada por la detección de agentes infecciosos extraños o por efectos del daño tisular. Sin embargo, algunas enfermedades graves como la neurodegeneración, la aterosclerosis, la diabetes y el cáncer están relacionadas con la inflamación crónica a largo plazo inducida por el estrés y que se produce como respuesta al estrés celular provocado por alteraciones de la fisiología normal. Por desgracia, los sensores y efectores fundamentales de la inflamación inducida por el estrés siguen siendo un misterio. El proyecto DESTRESS, financiado con fondos europeos, explorará la función y el comportamiento de los llamados «receptores de necrosis», miembros de la familia de receptores de factores de necrosis tumoral, como integradores de la inflamación inducida por el estrés para desvelar la composición de sus complejos de señalización, reorientar la investigación y posibilitar el tratamiento eficaz de numerosas enfermedades asociadas al estrés celular.
Objetivo
Inflammation is initiated in response to the detection of foreign entities, called PAMPs derived from infectious agents, or due to the release of intracellular contents, called DAMPs, due to serious tissue damage (i.e. necrosis). However, inflammation can also be initiated in response to Cell Stress (e.g. ER stress, cytoplasmic stress, mitochondrial stress) resulting from perturbations in normal physiology, but how cellular stress is converted to inflammatory outputs is very poorly understood. Many diseases are associated with chronic long-term inflammation (e.g. cancer, obesity, neurodegeneration, diabetes), which is a compounding factor in these conditions that can accelerate disease progression, but the inflammation seen in these conditions does not have an obvious infectious (PAMP) or acute injury (DAMP) cause. Instead, these diseases are frequently associated with persistent cell/tissue stress (e.g. due to misfolded proteins, elevated dietary fats, or metabolic stress) arising from persistent ER or cytoplasmic stress, that is likely to serve as a key driver of inflammation in these settings. However, the key sensors and effectors of stress-induced inflammation remain enigmatic.
Based on our recent observations, I wish to explore the hypothesis that members of the 'Death Receptor' subset of the TNF receptor family serve as stress-associated molecular patterns (SAMPs), becoming upregulated and/or activated in response to divergent forms of ER and cytoplasmic stress, leading to inflammation. Here, we will explore the role of Death Receptors as putative SAMPs, how they are activated by stress, the composition of their stress-induced signaling complexes, and the potential to suppress stress-induced inflammation through targeting these receptors. Understanding how Cell Stress initiates inflammation will open up a new frontier in inflammation research and identify new molecular targets for the treatment of chronic inflammation associated with multiple diseases.
Ámbito científico
Palabras clave
Programa(s)
Régimen de financiación
ERC-ADG - Advanced GrantInstitución de acogida
D02 CX56 DUBLIN 2
Irlanda