P2X1 transgenic mice

We have generated transgenic mice overexpressing the human P2X1 ion channel in the megakaryocytic cell lineage. Platelets from transgenic mice exhibited a gain of P2X1 ionotropic activity as determined by more prominent P2X1– mediated Ca2+ influx and platelet shape change.

P2X1 overexpression enhanced platelet secretion and aggregation evoked by collagen, convulxin, a GPVI-selective agonist, or the thromboxane A2 mimetic U46619.

In contrast, these platelet responses to ADP and thrombin were normal.

Hence, the platelet P2X1 ion channel plays a role in hemostasis and thrombosis through its participation in collagen-, thromboxane A2 and shear stress-triggered platelet responses. Activation of the ERK2 pathway is instrumental in these processes.

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DUSP3 KO mice

Dual-specificity phosphatase 3 (DUSP3) is implicated in platelet signaling and thrombosis. This phosphatase is highly expressed in human and mouse platelets. Platelets from DUSP3-deficient mice displayed a selective impairment of aggregation and granule secretion mediated through the collagen receptor glycoprotein VI (GPVI) and the C-type lectin-like receptor 2 (CLEC-2).

DUSP3-deficient mice were more resistant to collagen- and epinephrine-induced thromboembolism, compared to wild-type mice.

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Drug-induced toxic valvulopathy rabbit model

This model is unique given the oral instead of parenteral administration of the toxic agent.

We have demonstrated, for the first time that high dose long-term oral administration of serotonin can lead to valvular heart disease in rabbits. The tricuspid valve was commonly affected with moderate-to-severe regurgitation in all serotonin treated rabbits. The left-sided valves were less frequently and severely involved in the disease process.

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Abdominal aortic aneurysm rat model

An experimental model of unruptured AAA was developed by infusion of porcine elastase into rat aorta. Elastin degradation leads to dilation of the aorta, inflammatory infiltration of the abdominal wall and an intraluminal thrombus, corresponding to AAA in human.

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Thrombosis mouse models

We developed various thrombosis mouse models:

In this model, a thrombus is created by FeCl3-induced endothelium lesion in exposed vessels. The process is monitored by a miniature ultrasonic flow probe (0.5VB, Transonic systems), connected to a flowmeter (T106, Transonic systems) placed around the vessel to measure blood flow in the isolated carotid artery. The benefits of this model are its relative ease of implementation, low cost and non-requirement of a specialized laser.

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In this model, activation of the photochemical rose bengal with green light leads to thrombus formation. This process is monitored by real-time fluorescence microscopy.

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In this model, a high-energy laser induces thrombus formation in the cremaster arterioles.

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In this model, pulmonary embolism is induced by intravenous injection of a mixture of collagen and epinephrine or thromboplastin. This leads to widespread platelet activation and subsequent mortality, attributable to micro-thrombi in lung microvessels.

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Artherosclerosis mouse model

The genetic ablation of apoE (apolipoprotein) leads to the development of complex vascular lesions, comparable to those in humans. Lesions are observed in the aortic root, the brachiocephalic (innominate) artery and other branches of the aorta, as well as in the pulmonary and carotid arteries.

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Preclinical imaging

Logo_Logo-autres_GIGAOur GIGA platforms offer advanced preclinical functional and anatomical imaging solutions for a broad spectrum of application fields.

Our range of techniques includes:

Magnetic resonance imaging (MRI) scanners use strong magnetic fields and radio-waves to visualize detailed internal structures. Images are obtained in vivo with very high spatial and temporal resolution, good contrast for brain and soft tissues. MRI can be used in a wide variety of applications including anatomical, functional (fMRI) and molecular imaging for medical diagnosis, staging of disease and for follow-up without exposure to ionizing radiation.

Our system, Agilent MicroMRI 9,4T 310 ASR, is equipped with a technical imaging unit (MINERVE). It ensures the admission and extraction of anesthetic gas, thermoregulation of the study subject and monitoring of vital signs such as respiratory and cardiac frequencies.

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Computed Tomography (CT) is a non-destructive technique that yields structural and anatomical high-resolution 3D images with limited or no sample preparation required. This imaging modality complements the metabolic or functional images obtained with PET.

Being equipped with two beds for mice (25 mm) and rats (75 mm), our system, the TriFoil Imaging eXplore CT 120 micro-CT, is designed to visualize, quantify and characterize anatomical parameters in small animals. The system is also equipped with a technical imaging unit (MINERVE), ensuring the admission and extraction of anesthetic gas, thermoregulation of the study subject and monitoring of vital signs such as respiratory and cardiac frequencies.

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Positron Emission Tomography (PET) has the sensitivity at picomolar level to visualize molecular processes in 3D. In vivo PET imaging with labelled lead compounds will help to select the best one for clinical trials.

 

The technique allows:

  • The collection of quantitative and dynamic biodistribution data (e.g. micro-dosing studies) at an early stage of the clinical development: dynamic data for in-depth kinetic modeling, online blood measurements and in-brain positron-emission measurements
  • Detailed drug occupancy studies (proof of targets, mechanism, efficacy, pharmacokinetics, biodistribution)
  • Concentration analysis of targeted analytes after having developed and validated a dedicated method using microdialysis, a technique used for continuous measurement of free, bound analyte concentrations in the extracellular fluid. Analytes may include endogenous molecules (e.g. neurotransmitter, hormones, glucose, etc.) to assess their biochemical functions in the body, or exogenous compounds (e.g. pharmaceuticals) to determine their distribution within the body)

We are authorized to conduct research programs with classical (18F-FDG) and original radiotracers. Furthermore, we have developed expertise in experimental design, data collection, correction and modeling for kinetic analysis.

Being equipped with two beds for mice (25 mm) and rats (75 mm), our system, the Siemens Concorde FOCUS 120 micro-PET, is designed to visualize, quantify and characterize anatomical parameters in small animals. The system is also equipped with a technical imaging unit (MINERVE), ensuring the admission and extraction of anesthetic gas, thermoregulation of the study subject and monitoring of vital signs such as respiratory and cardiac frequencies.

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Our equipment includes the high-resolution, high-frequency ultrasound imaging system Vevo 2100 (Visualsonics). This is a non-invasive, in vivo micro imaging system, enabling visualization, assessment and measurement of anatomical structures and hemodynamic function in longitudinal studies for small animal phenotyping.

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The Xenogen IVIS 200 system is a highly sensitive and flexible system to trace bioluminescent reporter genes both in vivo and in vitro. It allows non-invasive longitudinal monitoring of disease progression, cell trafficking and gene expression patterns in living animals. By performing spectral fluorescence imaging, it allows the simultaneous use of bioluminescence and fluorescence imaging.

Bioluminescence imaging uses the enzyme, luciferase, that can be inserted into the genome of cancer cells or the cells you wish to track. Once these cells are implanted within mice, a tail vein or intra-peritoneal injection of luciferin (luciferase substrate) allows to follow their distribution ex vivo without euthanasia.

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Intravital microscopy is an extremely powerful tool that enables imaging several biological processes in living animals. In particular, to analyze:

 

 

  • Recruitment processes of leukocytes and platelets on microvessel endothelia
  • Bacterial adhesion on the microvessel endothelia
  • Thrombi and vascular occlusion formation
  • Lymphocytes migration to lymph nodes and lymphocytes adhesion to endothelia

Our equipment includes a motorized Olympus Cell R (Upright) microscope with EMCCD camera, controlled via the Slidebook software.

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PXI X-RAD SmART Image Guided Irradiator combines 3D imaging with highly accurate radiotherapy for Small Animals: mice, rats and rabbits. It combines a user friendly interface with state-of-the-art Monte Carlo calculation algorithms to rapidly devise treatment plans.

The system is fully integrated, with automated CT-CT registration, allowing, Image Guided Radiotherapy for precise tumor/organ localization. The integrated treatment planning enables rapid and highly conformal radiotherapy treatments, with collimator from 1 mm to 10 cm in round and non-round shapes, to be delivered in any scenario, ranging from simple subcutaneous xenografts to complex metastatic models or to develop non tumoral model as radiation-induced injury for a specific purpose.

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