Pathologie moléculaire

Résumé

La pathologie moléculaire est l'étude du rôle des biomolécules dans la genèse des maladies humaines. Ce champ scientifique et clinique est donc proche de biologie moléculaire et de la pathologie humaine et vétérinaire. Notes et références Voir aussi

Pathologie ** Pathologie clinique ** Anatomo-pathologie

Catégorie:Spécialité médicale Catégorie:Biologie moléculaire Catégorie:Pathologie Catégorie:Pathologie humaine

Source officielle

https://fr.wikipedia.org/wiki/Pathologie_mol%C3%A9culaire

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Publications associées (13)

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Concepts associés (13)

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Cours associés (3)

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Séances de cours associées (3)

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The recognition of pathogen-derived nucleic acids is a critical mechanism by which the innate immune system detects viral infection. Upon activation, nucleic acid sensors initiate the expression of type I interferons and other inflammatory mediators, subsequently leading to potent antiviral immune responses. However, erroneous detection of nucleic acids can have deleterious consequences for the host by inducing the development of certain autoinflammatory disorders. Inappropriate sensing of self- nucleic acids underlies a spectrum of monogenic disease referred to as type interferonopathies, including the Aicardi-Goutières syndrome (AGS). These disorders are often driven by mutations in genes encoding for components of nucleic acid recognition pathways, thereby resulting in the constitutive activation of type I interferon responses. Insight into the molecular pathology of AGS has highlighted promising new targets that may be harnessed for the development of novel therapeutics to counter this disorder. Stimulator of interferon genes (STING) - a central adaptor of the cytosolic DNA sensing pathway - has been strongly implicated in the pathogenesis of distinct inflammatory disorders, including AGS. Therefore, pharmacological inhibition of STING presents a promising approach for the development of potent treatment strategies against these and potentially other STING-mediated, autoinflammatory diseases. Performing a cell-based small-molecule screen, we identified and characterized two series of compounds, which potently and selectively inhibit STING through a mechanism that blocks the activation-induced palmitoylation of STING. The identified small-molecules mediate this inhibition through covalent binding to a transmembrane predicted cysteine residue (Cys91) - a palmitoylation site required for STING activation. Using the inhibitors, we show that the palmitoylation of STING mediates the formation of multimeric complexes at the Golgi and the subsequent recruitment and activation of the direct downstream kinase TBK1. We also provide evidence that representatives of both identified compound classes potently inhibit STING-induced expression of inflammatory cytokines including type I interferon, in human and mouse cells. Furthermore, we also demonstrate that the identified STING inhibitors attenuate autoinflammatory disease features in a mouse model of AGS. Taken together, this work uncovers a small-molecule mediated mechanism to inhibit STING and demonstrates the pharmacological potential of targeting STING for the treatment of type I interferon driven disease such as AGS.

EPFL2019

Chargement

Microfluidic systems for in-flow bioanalytes collection

Pierre-Emmanuel Marie Thiriet

Microfluidic is an ensemble of technologies and methods that permits the handling and analysis of minute volumes of samples in short timescales. Since its introduction it revealed a remarkable potential to unveil novel biological mechanisms. The small volumes involved in microchannels shortens reaction time and foster interactions between bioanalytes. Furthermore, the reduced footprint of the microfluidic channels also allows the integration of different modules within the same chip, each performing a dedicated step of a complex procedure, in what was defined as a lab-on-a-chip (LOC) platform. The use of 3D dimensional particles in such devices serve a double purpose: the manipulation of biological sample such as single cells in suspension and the introduction of microbeads that exhibits high surface-to-volume ratios and hence improved analyte collection.In this thesis, we present the development of new tools for the accurate manipulation of microparticles in microfluidic channels and their efficient exposure to flow. Microbeads or single cells were immobilized on-chip via a combination of hydrodynamic and dielectrophoretic (DEP) effects. Following their trapping, single-cells could be selectively released and recovered off-chip for further expansion and characterization. A transcriptomic analysis of recovered cells revealed marginal alteration of their molecular profile upon exposure to DEP forces and thus validated the potential of our technology for the assessment of single-lymphocytes properties. The efficient analyte collection achieved by microfluidic systems could benefit the field of diagnostics through the introduction of two distinct platforms. The first employs DEP forces to carry out the simultaneous detection of two acute kidney injury markers, NGAL and Cystatin C, in a minimally diluted buffer. High aspect-ratio three-dimensional electrodes were integrated in a microfluidic channel and could generate sufficient forces to retain functionalized beads against the flow of reagents for a 15 minutes-long incubation. The second introduces a novel approach based on DNA barcodes and toe-hold mediated strand displacement to perform the rapid readout of highly multiplexed immunoassays. The signal acquisition takes place in a wide microchamber crowded with mechanical traps stopping the beads at dedicated locations, its duration could be shorten down to 3 minutes per marker, with a throughput approaching 20 markers per hour.The obtained results demonstrated the potency of microfluidic platform for the manipulation and analysis of microparticles in-flow and paves the way for the development of a novel generation of highly integrated lab-on-a-chip systems.

EPFL2022

Chargement

Molecular profiling and functional analysis of macrophage-derived tumour extracellular vesicles

Tim Beltraminelli

Extracellular vesicles (EVs) are nanosized vesicles released by virtually all cell types. Increasing data suggest that EVs function in the regulation of intercellular communication both in physiological and pathological states. In cancer biology, mounting evidence suggests that cancer cell-derived EVs directly modulate several aspects of tumour progression by acting on both cancer cells and tumour-associated stromal cells. In addition to cancer cells, the tumour microenvironment (TME) also features an intertwined ensemble of recruited host-derived cells. Tumour-associated macrophages (TAMs) often infiltrate tumours in high numbers, thus representing one of the major host-derived cell populations. The involvement of TAMs in cancer progression has been extensively documented. It is well established that according to their polarisation state, TAMs can exert both pro- and anti-tumoural functions. However, under the influence of cancer cell-derived factors TAMs often acquire a phenotype that fosters tumour progression by supporting angiogenesis, metastasis and immunosuppression. While the role of secreted soluble factors contributing to the pro- and anti-tumoural functions of TAMs is well characterised, the molecular composition, properties, and effects of TAM-derived EVs (TAM-EVs) in the TME are poorly understood. In this thesis, I studied TAM-EVs produced in intact mouse tumours. We developed a methodology for the enrichment, quantification, and selective isolation of TAM-EVs produced in the TME. Furthermore, we performed comprehensive proteomic and lipidomic analyses of tumour-derived EVs and identified molecular signatures indicative of a role for TAM-EVs in immune response and lipid metabolism. Whereas source TAMs display a phenotype consistent with immunosuppressive functions, TAM-EVs have a pro-inflammatory and immune-stimulatory molecular signature. Indeed, TAM-EV-enriched preparations promoted T-cell proliferation and activation ex vivo and modulated arachidonic acid metabolism of cancer cells by inhibiting the production of the immunosuppressive PGE2 while favouring the secretion of pro-inflammatory thromboxane. Therefore, TAM-EVs might have the potential to stimulate, rather than limit, anti-tumour immunity. I also showed that while portraying some similarities with EVs of in vitro-polarised macrophages, TAM-EVs isolated from the TME present distinctive molecular profiles, suggesting that simplistic in vitro models do not faithfully recapitulate the complexity of the TME dynamics. Overall, this work emphasises the importance of studying TAM-EVs in their physiological context and identifies a potential role for TAM-EVs in favouring the development of an anti-tumoural immune microenvironment. Findings from this work extend our knowledge of the multifaceted role of TAMs in tumour biology.

EPFL2020

Chargement

Molecular profiling and functional analysis of macrophage-derived tumour extracellular vesicles

Tim Beltraminelli

EPFL2020

Microfluidic systems for in-flow bioanalytes collection

Pierre-Emmanuel Marie Thiriet

EPFL2022

EPFL2019