GIUV2026-038
The Inflammasome Signaling and Cell Death Research Group aims to investigate the molecular mechanisms that regulate inflammasome activation and their interplay with distinct cell death programs, as well as their contribution to the pathophysiology of inflammatory and tumor-related diseases.
Inflammasomes are multiprotein complexes of the innate immune system that assemble in response to cellular damage or stress signals (DAMPs and PAMPs) and function as signaling platforms for caspase-1 activation. Canonically, these complexes are composed of a sensor receptor, an adaptor protein ASC (Apoptosis-associated speck-like protein containing a CARD) and procaspase-1. Activation of caspase-1 leads to the processing of proinflammatory cytokines such as IL-1b and IL-18, as well as the cleavage of gasdermin D, thereby triggering pore formation in the plasma membrane and cell death by pyroptosis. Although multiple inflammasomes have been described depending on the initiating sensor receptor and have been implicated in a wide range of pathologies, current knowledge has largely focused on the NLRP3 inflammasome, while others such as NLRP6 or AIM2 remain less characterized.
In this context, the...The Inflammasome Signaling and Cell Death Research Group aims to investigate the molecular mechanisms that regulate inflammasome activation and their interplay with distinct cell death programs, as well as their contribution to the pathophysiology of inflammatory and tumor-related diseases.
Inflammasomes are multiprotein complexes of the innate immune system that assemble in response to cellular damage or stress signals (DAMPs and PAMPs) and function as signaling platforms for caspase-1 activation. Canonically, these complexes are composed of a sensor receptor, an adaptor protein ASC (Apoptosis-associated speck-like protein containing a CARD) and procaspase-1. Activation of caspase-1 leads to the processing of proinflammatory cytokines such as IL-1b and IL-18, as well as the cleavage of gasdermin D, thereby triggering pore formation in the plasma membrane and cell death by pyroptosis. Although multiple inflammasomes have been described depending on the initiating sensor receptor and have been implicated in a wide range of pathologies, current knowledge has largely focused on the NLRP3 inflammasome, while others such as NLRP6 or AIM2 remain less characterized.
In this context, the group focuses on the identification of chemical modulators capable of regulating the activation of inflammasomes such as NLRP6 and AIM2, as well as on their functional characterization. To this end, the group combines high-throughput screening strategies, recombinant protein production, and mechanistic studies in cellular models, complemented by inflammatory in vivo models as proof of concept. In addition, these approaches allow exploration of the specific contribution of these inflammasomes to complex diseases, including cancer.
In parallel, the laboratory is also interested in the study of the adaptor protein ASC, based on the principal investigator¿s previous experience in the development of the ASC-specific inhibitor MM01. Beyond its role as an essential intracellular adaptor for caspase-1 activation, ASC forms filamentous structures with prion-like properties that organize into so-called ASC specks. The group investigates both the value of ASC as a biomarker in inflammatory diseases and the role of extracellular ASC specks released upon inflammasome activation, which act as potent amplifiers of inflammatory signaling and contribute to the propagation of inflammation between cells and tissues. In this regard, ASC is conceived not only as a molecular scaffold but also as a multimodal platform at the crossroads of inflammation, apoptosis, autophagy, and antiviral signaling pathways.
Finally, a transversal line of research addresses the crosstalk between inflammasomes and distinct regulated cell death programs, including pyroptosis and apoptosis. The goal is to understand how the activation of these signaling platforms determines cell fate and how modulation of these processes may open new therapeutic opportunities.
Overall, the group aims to contribute to a global understanding of inflammasome signaling and cell death by identifying novel regulatory nodes and providing experimental evidences for the development of therapeutic strategies aimed at modulating the innate inflammatory response.
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- Estudiar la implicación de los inflamasomas en enfermedades inflamatorias y cáncer.
- Búsqueda de moduladores de los diferentes inflamasomas, en particular del inflamasoma NLRP6 y AIM2.
- Explorar el papel de ASC como biomarcador y en particular, analizar el comportamiento de los specks de ASC como propagadores del proceso inflamatorio.
- Interplay between inflammasome activation and cell death.Analyze the interplay between inflammasome activation and distinct cell death programs, including pyroptosis and apoptosis, with the aim of understanding how these pathways converge and determine cell fate in relevant pathophysiological contexts.
- Characterize the activation mechanisms of inflammasomes.Characterize the mechanisms of inflammasome activation, with a particular focus on NLRP6 and AIM2, through the identification of novel chemical modulators and their functional analysis in cellular and in vivo models, in order to understand their contribution to inflammatory and pathological processes, including cancer.
- Role of the ASC adaptor protein in inflammatory signaling.Investigate the role of the adaptor protein ASC in inflammatory signaling, with special emphasis on the study of ASC specks as amplifiers and propagators of inflammation, as well as on their potential use as disease biomarkers.
| Name | Nature of participation | Entity | Description |
|---|---|---|---|
| MONICA SANCHO MEDINA | Director | Universitat de València | |
| Research team | |||
| MARIA DEL MAR ORZAEZ CALATAYUD | Collaborator | Universitat de València | |
| MARIA DEL MAR ORZAEZ CALATAYUD | Collaborator | Universitat de València | |
| CELIA PILAR MARTINEZ JIMENEZ | Collaborator | Universitat de València | |
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- Biochemistry and Molecular Biology
