Descripción del proyecto
El papel de los focos apoptóticos en la permeabilización de la membrana mitocondrial externa
La regulación de la muerte celular apoptótica es fundamental para el desarrollo, la función inmunitaria y la homeostasis tisular. La permeabilización de la membrana mitocondrial externa (MOMP, por sus siglas en inglés) resulta esencial para la ejecución de la apoptosis, y la comprensión de los mecanismos que median la MOMP es primordial para lograr una posible aplicación clínica de la apoptosis. Estudios recientes llevados a cabo por el laboratorio anfitrión han revelado que los dímeros proteicos Bax y Bak se organizan en focos apoptóticos específicos para inducir la MOMP. El proyecto APOSITE, financiado con fondos europeos, investigará la composición, la dinámica y la estructura de focos apoptóticos para dilucidar su papel esencial en la regulación de la apoptosis. Los investigadores aprovecharán su experiencia en muerte celular y tecnologías de imagenología avanzada. Este enfoque multidisciplinario promete responder a la pregunta de cómo Bax y Bak inducen la MOMP y contribuir a desarrollar moduladores de la apoptosis para aplicaciones médicas.
Objetivo
Apoptotic cell death is essential for development, immune function or tissue homeostasis, and it is often deregulated in disease. Mitochondrial outer membrane permeabilization (MOMP) is central for apoptosis execution and plays a key role in its inflammatory outcome. Knowing the architecture of the macromolecular machineries mediating MOMP is crucial for understanding their function and for the clinical use of apoptosis.
Our recent work reveals that Bax and Bak dimers form distinct line, arc and ring assemblies at specific apoptotic foci to mediate MOMP. However, the molecular structure and mechanisms controlling the spatiotemporal formation and range of action of the apoptotic foci are missing. To address this fundamental gap in our knowledge, we aim to unravel the composition, dynamics and structure of apoptotic foci and to understand how they are integrated to orchestrate function. We will reach this goal by building on our expertise in cell death and cutting-edge imaging and by developing a new analytical pipeline to:
1) Identify the composition of apoptotic foci using in situ proximity-dependent labeling and extraction of near-native Bax/Bak membrane complexes coupled to mass spectrometry.
2) Define their contribution to apoptosis and its immunogenicity and establish their assembly dynamics to correlate it with apoptosis progression by live cell imaging.
3) Determine the stoichiometry and structural organization of the apoptotic foci by combining single molecule fluorescence and advanced electron microscopies.
This multidisciplinary approach offers high chances to solve the long-standing question of how Bax and Bak mediate MOMP. APOSITE will provide textbook knowledge of the mitochondrial contribution to cell death and inflammation. The implementation of this new analytical framework will open novel research avenues in membrane and organelle biology. Ultimately, understanding of Bax and Bak structure/function will help develop apoptosis modulators for medicine.
Ámbito científico
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Régimen de financiación
ERC-COG - Consolidator GrantInstitución de acogida
50931 Koln
Alemania