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1. HRAS germline mutations impair LKB1/AMPK signaling and mitochondrial homeostasis in Costello syndrome models

Author

Laetitia Dard, Christophe Hubert, Pauline Esteves, Wendy Blanchard, Ghina Bou About, Lyla Baldasseroni, Elodie Dumon, Chloe Angelini, Mégane Delourme, Véronique Guyonnet-Dupérat, Stéphane Claverol, Laura Fontenille, Karima Kissa, Pierre-Emmanuel Séguéla, Jean-Benoît Thambo, Lévy Nicolas, Yann Herault, Nadège Bellance, Nivea Dias Amoedo, Frédérique Magdinier, Tania Sorg, Didier Lacombe, and Rodrigue Rossignol

Subjects
Metabolism, Medicine
Abstract

Germline mutations that activate genes in the canonical RAS/MAPK signaling pathway are responsible for rare human developmental disorders known as RASopathies. Here, we analyzed the molecular determinants of Costello syndrome (CS) using a mouse model expressing HRAS p.G12S, patient skin fibroblasts, hiPSC-derived human cardiomyocytes, a HRAS p.G12V zebrafish model, and human fibroblasts expressing lentiviral constructs carrying HRAS p.G12S or HRAS p.G12A mutations. The findings revealed alteration of mitochondrial proteostasis and defective oxidative phosphorylation in the heart and skeletal muscle of CS mice that were also found in the cell models of the disease. The underpinning mechanisms involved the inhibition of the AMPK signaling pathway by mutant forms of HRAS, leading to alteration of mitochondrial proteostasis and bioenergetics. Pharmacological activation of mitochondrial bioenergetics and quality control restored organelle function in HRAS p.G12A and p.G12S cell models, reduced left ventricle hypertrophy in CS mice, and diminished the occurrence of developmental defects in the CS zebrafish model. Collectively, these findings highlight the importance of mitochondrial proteostasis and bioenergetics in the pathophysiology of RASopathies and suggest that patients with CS may benefit from treatment with mitochondrial modulators.

Published
2022
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2. Soft windowing application to improve analysis of high-throughput phenotyping data.

Author

Hamed Haselimashhadi, Jeremy C. Mason, Violeta Muñoz-Fuentes, Federico López-Gómez, Kolawole O. Babalola, Elif F. Acar, Vivek Kumar, Jacqui White, Ann M. Flenniken, Ruairidh King, Ewan Straiton, John Richard Seavitt, Angelina Gaspero, Arturo Garza, Audrey E. Christianson, Chih-Wei Hsu, Corey L. Reynolds, Denise G. Lanza, Isabel Lorenzo, Jennie R. Green, Juan J. Gallegos, Ritu Bohat, Rodney C. Samaco, Surabi Veeraragavan, Jong Kyoung Kim, Gregor Miller, Helmut Fuchs, Lillian Garrett, Lore Becker, Yeon Kyung Kang, David Clary, Soo Young Cho, Masaru Tamura, Nobuhiko Tanaka, Kyung Dong Soo, Alexandr Bezginov, Ghina Bou About, Marie-France Champy, Laurent Vasseur, Sophie Leblanc, Hamid Meziane, Mohammed Selloum, Patrick T. Reilly, Nadine Spielmann, Holger Maier, Valérie Gailus-Durner, Tania Sorg, Hiroshi Masuya, Yuichi Obata, Jason D. Heaney, Mary E. Dickinson, Wolfgang Wurst, Glauco P. Tocchini-Valentini, Kevin C. Kent Lloyd, Colin McKerlie, Je Kyung Seong, Yann Herault, Martin Hrabé de Angelis, Steve D. M. Brown, Damian Smedley, Paul Flicek, Ann-Marie Mallon, Helen E. Parkinson, and Terrence F. Meehan

Published
2020
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3. Loss of low-molecular-weight protein tyrosine phosphatase shows limited improvement in glucose tolerance but causes mild cardiac hypertrophy in mice

Author

Sharon, Jensen-Cody, Erin S, Coyne, Xunshan, Ding, Anu, Sebin, Jen, Vogel, Jaclyn, Goldstein, Thomas W, Rosahl, Heather H, Zhou, Hugues, Jacobs, Marie-France, Champy, Ghina Bou, About, Saswata, Talukdar, and Yingjiang, Zhou

Subjects
Physiology, Endocrinology, Diabetes and Metabolism, Mice, Obese, Cardiomegaly, Diet, High-Fat, Mice, Inbred C57BL, Mice, Glucose, Diabetes Mellitus, Type 2, Thinness, Physiology (medical), Animals, Insulin, Insulin Resistance, Protein Tyrosine Phosphatases
Abstract

Insulin resistance is a major public health burden that often results in other comorbidities including type 2 diabetes, nonalcoholic fatty liver disease (NAFLD), and cardiovascular disease. An insulin sensitizer has the potential to become a disease-modifying therapy. It remains an unmet medical need to identify therapeutics that target the insulin signaling pathway to treat insulin resistance. Low-molecular-weight protein tyrosine phosphatase (LMPTP) negatively regulates insulin signaling and has emerged as a potential therapeutic target for insulin sensitization. Genetic studies have demonstrated that LMPTP is positively associated with obesity in humans and promotes insulin resistance in rodents. A recent study showed that pharmacological inhibition or genetic deletion of LMPTP protects mice from high-fat diet-induced insulin resistance and diabetes. Here, we show that loss of LMPTP by genetic deletion has no significant effects on improving glucose tolerance in lean or diet-induced obese mice. Furthermore, our data demonstrate that LMPTP deficiency potentiates cardiac hypertrophy that leads to mild cardiac dysfunction. Our findings suggest that the development of LMPTP inhibitors for the treatment of insulin resistance and type 2 diabetes should be reevaluated, and further studies are needed to characterize the molecular and pathophysiological role of LMPTP.

Published
2022
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4. Soft windowing application to improve analysis of high-throughput phenotyping data

Author

Alexandr Bezginov, Paul Flicek, Masaru Tamura, Masuya Hiroshi, Mohammed Selloum, Yeon Kyung Kang, Herault Yann, Rodney C. Samaco, Ann-Marie Mallon, Helen Parkinson, Soo Young Cho, Ghina Bou About, Nadine Spielmann, Arturo Garza, Glauco P. Tocchini-Valentini, Gregor Miller, Obata Yuichi, John R. Seavitt, Surabi Veeraragavan, Jennie R. Green, Ewan Straiton, Marie-France Champy, Ann M Flenniken, Je Kyung Seong, Kyung Dong Soo, Isabel Lorenzo, Kevin C K Lloyd, Terrence F. Meehan, Vivek Kumar, Lillian Garrett, Damian Smedley, Elif F. Acar, Hamid Meziane, Ritu Bohat, Lore Becker, Sophie Leblanc, Denise G. Lanza, Angelina Gaspero, Audrey E. Christianson, Juan Gallegos, Wurst Wolfgang, Chih-Wei Hsu, Hamed Haselimashhadi, Colin McKerlie, Ruairidh King, Stephen D.M. Brown, Dave Clary, Nobuhiko Tanaka, Tania Sorg, Helmut Fuchs, Jason D. Heaney, Jacqui White, Jeremy Mason, Martin Hrabé de Angelis, Federico López-Gómez, Laurent Vasseur, Valerie Gailus-Durner, Holger Maier, Corey L. Reynolds, Violeta Muñoz-Fuentes, Mary E Dickinson, K. O. Babalola, Patrick T. Reilly, Jong Kyoung Kim, Schwartz, Russell, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)

Subjects
Statistics and Probability, Computer science, Bioinformatics, Pipeline (computing), [SDV]Life Sciences [q-bio], Disease, computer.software_genre, 01 natural sciences, Biochemistry, Article, Mathematical Sciences, Set (abstract data type), Reduction (complexity), 010104 statistics & probability, 03 medical and health sciences, Mice, 0302 clinical medicine, Resampling, Information and Computing Sciences, False positive paradox, Genetics, Animals, Humans, 0101 mathematics, Molecular Biology, Throughput (business), ComputingMilieux_MISCELLANEOUS, Genetic Association Studies, 030304 developmental biology, Linkage (software), 0303 health sciences, Population Health, Biological Sciences, Computer Science Applications, Computational Mathematics, Phenotype, Computational Theory and Mathematics, Data mining, computer, 030217 neurology & neurosurgery, Software
Abstract

Motivation High-throughput phenomic projects generate complex data from small treatment and large control groups that increase the power of the analyses but introduce variation over time. A method is needed to utlize a set of temporally local controls that maximizes analytic power while minimizing noise from unspecified environmental factors. Results Here we introduce ‘soft windowing’, a methodological approach that selects a window of time that includes the most appropriate controls for analysis. Using phenotype data from the International Mouse Phenotyping Consortium (IMPC), adaptive windows were applied such that control data collected proximally to mutants were assigned the maximal weight, while data collected earlier or later had less weight. We applied this method to IMPC data and compared the results with those obtained from a standard non-windowed approach. Validation was performed using a resampling approach in which we demonstrate a 10% reduction of false positives from 2.5 million analyses. We applied the method to our production analysis pipeline that establishes genotype–phenotype associations by comparing mutant versus control data. We report an increase of 30% in significant P-values, as well as linkage to 106 versus 99 disease models via phenotype overlap with the soft-windowed and non-windowed approaches, respectively, from a set of 2082 mutant mouse lines. Our method is generalizable and can benefit large-scale human phenomic projects such as the UK Biobank and the All of Us resources. Availability and implementation The method is freely available in the R package SmoothWin, available on CRAN http://CRAN.R-project.org/package=SmoothWin. Supplementary information Supplementary data are available at Bioinformatics online.

Published
2020
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5. Ultrasound-Guided Approaches to Improve Orthotopic Mouse Xenograft Models for Hepatocellular Carcinoma

Author

Yann Herault, Emilie Thiebault, Thomas F. Baumert, Ghina Bou About, Tania Sorg, Laurent Monassier, Hugues Jacobs, Eric Robinet, Marie Wattenhofer-Donzé, Alain Guimond, Institut de Recherche sur les Maladies Virales et Hépatiques (IVH), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de neurobiologie et pharmacologie cardiovasculaire (LNPCV), Université de Strasbourg (UNISTRA), Laboratoire de pharmacologie et toxicologie neurocardiovasculaire (LPTNC), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Institut Clinique de la Souris (ICS), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), French National Infrastructure for Mouse Phenogenomics (PHENOMIN), Institut de Chirurgie guidée par l'Image, and univOAK, Archive ouverte

Subjects
Cirrhosis, Huh-7, Sciences du Vivant [q-bio]/Cancer, Heterologous/instrumentation/*methods, Mice, 0302 clinical medicine, Liver Neoplasms, Experimental, Ultrasonics, Stage (cooking), 0303 health sciences, Sciences du Vivant [q-bio]/Ingénierie biomédicale, Liver Neoplasms, Liver Neoplasms/therapy, Sciences du Vivant [q-bio]/Biotechnologies, General Medicine, 3. Good health, Drug development, Hepatocellular carcinoma, Heterografts, medicine.drug, Carcinoma, Hepatocellular, Experimental/*therapy, Transplantation, Heterologous, [SDV.CAN]Life Sciences [q-bio]/Cancer, Ultrasonics/instrumentation/*methods, Hepatocellular/therapy, doxorubicin, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, echo-guided injection, medicine, Carcinoma, Distribution (pharmacology), Animals, Doxorubicin, orthotopic, 030304 developmental biology, Heterografts/*physiology, Transplantation, business.industry, echography, medicine.disease, digestive system diseases, hepatocarcinoma, Cancer research, business, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide. While curative approaches for early stage HCC exist, effective treatment options for advanced HCC are lacking. Furthermore, there are no efficient chemopreventive strategies to limit HCC development once cirrhosis is established. One challenge for drug development is unsatisfactory animal models. In this article, we describe an orthotopic xenograft mouse model of human liver cancer cell lines through image-guided injection into the liver. This technique provides a less invasive yet highly efficient approach to engraft human HCC into mouse liver. Similarly, image-guided injections are used to deliver chemotherapeutics locally, enabling reduction in potential systemic adverse effects, while reducing the required dose for a therapeutic effect. In summary, this image-guided strategy provides a novel and convenient approach to improve current HCC mouse models. (c) 2019 The Authors. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Published
2019
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6. An innovative combined immunization platform for personalized cancer immunotherapy

Author

Emilie Thiebault Peter, Tania Sorg, Robert Drillien, Jessica Matta, Ghina Bou About, Célia Matta, Jean-Marc Limacher, Benoit Petit-Demouliere, and David Moulaert

Subjects
Cancer Research, Immune system, Oncology, Cancer immunotherapy, Immunization, business.industry, medicine.medical_treatment, Immune checkpoint inhibitors, Immunology, medicine, Tumor specific, chemical and pharmacologic phenomena, business
Abstract

e14225 Background: Activity of immune checkpoint inhibitors relies mainly on the presence of an immune response directed against neoantigens resulting from tumor specific mutations. The induction and/or amplification of such an immune response is expected to increase the activity of these therapies. We describe here a novel immunization platform developed for the purpose of personalized cancer immunotherapy. This platform integrates a DNA vector coding for neoantigens, a live modified vaccinia of strain Ankara (MVA) used as a physiologic adjuvant and anti-CTLA-4 as a locally acting early immune checkpoint blocker. Methods: Immune potency was assessed in C57BL6 mice injected subcutaneously three times five days apart with an ovalbumine (OVA) expressing DNA vector (100 µg), either alone or in combination with increasing doses of MVA (up to 2.5x107 plaque forming units, pfu) and increasing doses of anti-CTLA-4 (up to 100 µg). OVA specific immune responses were measured by ELISpot. Anti-tumor efficacy was then investigated with a similar administration scheme in a therapeutic B16F10 mice melanoma model with a DNA vector coding for the B16F10-M30 tumor neoantigen. Results: At an optimal dose of 2.5x106 pfu, MVA significantly improved OVA specific immune response up to 10 times higher as compared to vector alone. Addition of CTLA-4 blockade further increased the magnitude of response, up to 30 times higher than with vector alone. Both MVA and CTLA-4 demonstrated a bell-shaped dose dependent effect. In tumor-bearing animals, 80% experienced durable tumor-free survival when treated with the combination therapy as compared to less than 20% in untreated animals or animals treated with each component independently. Treatment appeared feasible and well-tolerated. Conclusions: Neoantigen coding DNA vector, MVA and CTLA-4 immune checkpoint blockade, when co-administered in immunocompetent C57BL6 mice, acted synergistically to induce a cellular immune response. The same approach translated into a strong anti-tumoral response in an aggressive melanoma model. This combined immunization platform appears as a potential novel way to enhance clinical benefit from current immune checkpoint inhibitors.

Published
2019
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7. Nox4 genetic inhibition in experimental hypertension and metabolic syndrome

Author

Hugues Jacob, Lola Madeira, Yann Herault, Guillaume Pavlovic, Marie-France Champy, Laurent Monassier, Lahcen El Fertak, Marie-Christine Birling, Ghina Bou-About, Tania Sorg, John S. Mudgett, Benoit Petit-Demoulière, Estelle Ayme-Dietrich, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de pharmacologie et de toxicologie neurocardiovasculaire (LPTNC), Université de Strasbourg (UNISTRA), CHU Strasbourg, Merck Research Laboratories, Institut Clinique de la Souris, and univOAK, Archive ouverte

Subjects
0301 basic medicine, Blood Glucose, Male, Time Factors, Cardiac fibrosis, Blood Pressure, 030204 cardiovascular system & hematology, Angiotensin, NADPH oxydase, 0302 clinical medicine, Heart Rate, Metabolic Syndrome, Mice, Knockout, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Ventricular Remodeling, Angiotensin II, General Medicine, Pulse pressure, Angiotensine, Phenotype, NADPH Oxidase 4, Hypertension, cardiovascular system, Female, Cardiology and Cardiovascular Medicine, medicine.medical_specialty, Cardiomegaly, Diet, High-Fat, 03 medical and health sciences, Nox4, Métabolisme, Internal medicine, Diabetes mellitus, Heart rate, Renin–angiotensin system, medicine, Animals, Genetic Predisposition to Disease, Triglycerides, NADPH oxidase, business.industry, Myocardium, medicine.disease, Fibrosis, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, Endocrinology, Blood pressure, Metabolism, Heart failure, Metabolic syndrome, business, Reactive Oxygen Species, Biomarkers, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Summary Background Metabolic syndrome is a combination of symptoms including obesity, dyslipidaemia, glucose intolerance and hypertension. Oxidative stress appears to be a pathophysiological factor that links these signs and encourages progression towards heart failure and diabetes. Nox4 is a hydrogen peroxide nicotinamide adenine dinucleotide phosphate (NADPH) oxidase isoform – found in various cardiovascular cells and tissues, but also in tissues such as the liver – which is involved in glucose and lipid homeostasis. Aims To test whether inhibition of the Nox4 enzyme could improve blood pressure and metabolic parameters in mice receiving either angiotensin II or a high-fat diet. Methods Systolic and diastolic arterial pressures, pulse rate and heart rate were obtained in 24 male mice (12 wild-type [WT] and 12 Nox4–/–) before and during 14 days of angiotensin II infusion. After angiotensin II infusion, cardiac histological remodeling was assessed. Weight and biochemical parameters were measured in 18 male and 18 female mice (nine WT and nine Nox4–/– per gender) after 10 weeks on a standard chow diet, then 15 weeks on a high-fat diet. Glucose tolerance and insulin sensitivity were tested at age 25 weeks. Results Knock-out animals did not demonstrate a baseline blood pressure phenotype, but blocking Nox4 protected against angiotensin II-mediated arterial and pulse pressure increases. No protection against angiotensin II-induced cardiac fibrosis was observed. From a metabolic point of view, Nox4 inhibition reduced plasma triglycerides in male and female mice under a chow diet. However, Nox4 deletion did not affect the metabolic profile under a high-fat diet in males or females, but increased glucose intolerance in females. Conclusion Our data identify Nox4 as a key source of radical oxygen species involved in hypertension and some metabolic problems.

Published
2017
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8. Non-invasive quantitative imaging of hepatocellular carcinoma growth in mice by micro-CT using liver-targeted iodinated nano-emulsions

Author

Mohamed F. Attia, Hugues Jacobs, Tania Sorg, Alexandru Parlog, Eric Robinet, Isabelle Goncalves, Marie Wattenhofer-Donzé, Ghina Bou About, Thierry F. Vandamme, Nicolas Anton, Laboratoire de Conception et Application de Molécules Bioactives, Centre National de la Recherche Scientifique (CNRS), Conception et application de molécules bioactives (CAMB), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Laboratoire de Conception et Application de Molécules Bioactives (UMR 7199 CNRS/Université de Strasbourg), CNRS (UMR 7199), Laboratoire de Chimie des Systèmes Fonctionnels, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre for Integrative Biology - CBI (Inserm U964 - CNRS UMR7104 - IGBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institute of genetics and molecular and cellular biology, Institut Clinique de la Souris, Institut de Recherche sur les Maladies Virales et Hépatiques (IVH), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Quantitative imaging, Carcinoma, Hepatocellular, Halogenation, Nano emulsion, lcsh:Medicine, Sciences du Vivant [q-bio]/Médecine humaine et pathologie, Article, 03 medical and health sciences, Mice, 0302 clinical medicine, Cell Line, Tumor, Carcinoma, medicine, Animals, Humans, Nanotechnology, lcsh:Science, Cell Proliferation, Ultrasonography, Multidisciplinary, medicine.diagnostic_test, business.industry, Non invasive, Liver Neoplasms, lcsh:R, Cancer, Magnetic resonance imaging, X-Ray Microtomography, medicine.disease, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, Cell Transformation, Neoplastic, Liver, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, Hepatocyte, Emulsions, Female, lcsh:Q, Nuclear medicine, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Hepatocellular carcinoma (HCC) is the only cancer for which non-invasive diagnosis is recognized by international guidelines. Contrast agent free ultrasound imaging, computed tomography (CT) and/or magnetic resonance imaging are techniques used for early detection and confirmation. Clinical evidence depicts that CT is 30% less precise as compared to MRI for detection of small tumors. In our work, we have reported some novel tools that can enhance the sensitivity and precision of CT applied to preclinical research (micro-CT). Our system, containing non-toxic nano-droplets loaded with iodine has high contrasting properties, liver and hepatocyte specificity and strong liver persistence. Micro-CT was performed on HCC model implanted in nude mice by intrahepatic injection. Contrast agent was administrated intravenously. This method allows an unprecedented high precision of detection, quantitative measurement of tumor volume and quantitative follow-up of the tumor development.

Published
2017
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9. Physiological Expression of AMPKγ2 Mutation Causes Wolff-Parkinson-White Syndrome and Induces Kidney Injury in Mice

Author

Benoit Petit-Demoulière, Marie-France Champy, John S. Mudgett, Laurent Monassier, Li-Jun Ma, Hong-Ping Guan, Robert W. Myers, Yann Herault, Wen Feng, Cai Li, Hongwu Wang, Mark D. Erion, Hugues Jacobs, Ghina Bou-About, Roger Askew, Ku Lu, Xiaodong Yang, David E. Kelley, Guillaume Pavlovic, Tania Sorg, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Institut Clinique de la Souris, French National Infrastructure for Mouse Phenogenomics (PHENOMIN), Laboratoire de pharmacologie et de toxicologie neurocardiovasculaire (LPTNC), Université de Strasbourg (UNISTRA), and Merck Research Laboratories

Subjects
Male, 0301 basic medicine, medicine.medical_specialty, AMP-activated kinase (AMPK), Transgene, Apoptosis, AMP-Activated Protein Kinases, 030204 cardiovascular system & hematology, Biology, Sciences du Vivant [q-bio]/Médecine humaine et pathologie, Kidney, medicine.disease_cause, Biochemistry, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, AMP-activated protein kinase, glycogen storage disease, kidney metabolism, Internal medicine, insulin resistance, medicine, Animals, Glycogen storage disease, Gene Knock-In Techniques, Renal Insufficiency, liver metabolism, Molecular Biology, Inflammation, Mutation, Glycogen, diabetes, Kidney metabolism, AMPK, Cell Biology, medicine.disease, Mice, Inbred C57BL, Disease Models, Animal, Metabolism, 030104 developmental biology, Endocrinology, medicine.anatomical_structure, chemistry, biology.protein, Wolff-Parkinson-White Syndrome, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Mutations of the AMP-activated kinase gamma 2 subunit (AMPKγ2), N488I (AMPKγ2NI) and R531G (AMPKγ2RG), are associated with Wolff-Parkinson-White (WPW) syndrome, a cardiac disorder characterized by ventricular pre-excitation in humans. Cardiac-specific transgenic overexpression of human AMPKγ2NI or AMPKγ2RG leads to constitutive AMPK activation and the WPW phenotype in mice. However, overexpression of these mutant proteins also caused profound, non-physiological increase in cardiac glycogen, which might abnormally alter the true phenotype. To investigate whether physiological levels of AMPKγ2NI or AMPKγ2RG mutation cause WPW syndrome and metabolic changes in other organs, we generated two knock-in mouse lines on the C57BL/6N background harboring mutations of human AMPKγ2NI and AMPKγ2RG, respectively. Similar to the reported phenotypes of mice overexpressing AMPKγ2NI or AMPKγ2RG in the heart, both lines developed WPW syndrome and cardiac hypertrophy; however, these effects were independent of cardiac glycogen accumulation. Compared with AMPKγ2WT mice, AMPKγ2NI and AMPKγ2RG mice exhibited reduced body weight, fat mass, and liver steatosis when fed with a high fat diet (HFD). Surprisingly, AMPKγ2RG but not AMPKγ2NI mice fed with an HFD exhibited severe kidney injury characterized by glycogen accumulation, inflammation, apoptosis, cyst formation, and impaired renal function. These results demonstrate that expression of AMPKγ2NI and AMPKγ2RG mutations at physiological levels can induce beneficial metabolic effects but that this is accompanied by WPW syndrome. Our data also reveal an unexpected effect of AMPKγ2RG in the kidney, linking lifelong constitutive activation of AMPK to a potential risk for kidney dysfunction in the context of an HFD.

Published
2016
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10. Multimodal imaging of a humanized orthotopic model of hepatocellular carcinoma in immunodeficient mice

Author

Emilie Heuillard, Mourad Bouhadjar, Eric Robinet, Thierry F. Vandamme, Thomas Baumert, Philippe Choquet, Christophe Ferrand, Eugénie Dalimier, Céline Giraudeau, Mihaela Ignat, Véronique Lindner, Patrick Pessaux, Cynthia Calligaro, Ghina Bou About, Franck Blindauer, Michele Diana, Nicolas Anton, Gael Fouré, Hussein El-Saghire, Tao Wu, Tania Sorg, Jacques Marescaux, Jean-Philippe Dillenseger, Francine Gossé, Institut de Recherche sur les Maladies Virales et Hépatiques (IVH), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Kunming Medical University (KMU), L'Institut hospitalo-universitaire de Strasbourg (IHU Strasbourg), Institut National de Recherche en Informatique et en Automatique (Inria)-l'Institut de Recherche contre les Cancers de l'Appareil Digestif (IRCAD)-Les Hôpitaux Universitaires de Strasbourg (HUS)-La Fédération des Crédits Mutuels Centre Est (FCMCE)-L'Association pour la Recherche contre le Cancer (ARC)-La société Karl STORZ, CHU Strasbourg, Institut Clinique de la Souris, Les Hôpitaux Universitaires de Strasbourg (HUS), l'Institut de Recherche contre les Cancers de l'Appareil Digestif (IRCAD), Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), Conception et application de molécules bioactives (CAMB), Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), LLTech SAS Paris, Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Université de Franche-Comté (UFC), and Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)

Subjects
Male, 0301 basic medicine, Sorafenib, Carcinoma, Hepatocellular, metabolism, pathology, Sciences du Vivant [q-bio]/Médecine humaine et pathologie, Multimodal Imaging, Article, methods, Mice, 03 medical and health sciences, Optical coherence tomography, In vivo, Cell Line, Tumor, medicine, Animals, Humans, Doxorubicin, Luciferases, Ultrasonography, Multidisciplinary, medicine.diagnostic_test, business.industry, Liver Neoplasms, Magnetic resonance imaging, Hep G2 Cells, medicine.disease, Magnetic Resonance Imaging, 3. Good health, Transplantation, Disease Models, Animal, 030104 developmental biology, Hepatocellular carcinoma, Cancer research, Female, business, Neoplasm Transplantation, Preclinical imaging, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, medicine.drug
Abstract

The development of multimodal strategies for the treatment of hepatocellular carcinoma requires tractable animal models allowing for advanced in vivo imaging. Here, we characterize an orthotopic hepatocellular carcinoma model based on the injection of luciferase-expressing human hepatoma Huh-7 (Huh-7-Luc) cells in immunodeficient mice. Luciferase allows for an easy repeated monitoring of tumor growth by in vivo bioluminescence. The intrahepatic injection was more efficient than intrasplenic or intraportal injection in terms of survival, rate of orthotopic engraftment, and easiness. A positive correlation between luciferase activity and tumor size, evaluated by Magnetic Resonance Imaging, allowed to define the endpoint value for animal experimentation with this model. Response to standard of care, sorafenib or doxorubicin, were similar to those previously reported in the literature, with however a strong toxicity of doxorubicin. Tumor vascularization was visible by histology seven days after Huh-7-Luc transplantation and robustly developed at day 14 and day 21. The model was used to explore different imaging modalities, including microtomography, probe-based confocal laser endomicroscopy, full-field optical coherence tomography, and ultrasound imaging. Tumor engraftment was similar after echo-guided intrahepatic injection as after laparotomy. Collectively, this orthotopic hepatocellular carcinoma model enables the in vivo evaluation of chemotherapeutic and surgical approaches using multimodal imaging.

Published
2016
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11. Erythropoietin recapitulates hemodynamic features of hypoxia-induced pulmonary hypertension in mice

Author

Hugues Jacobs, Laurent Monassier, Ghina Bou About, Julien Becker, Patrick T. Reilly, Yann Herault, Lahcen El Fertak, Emilie Peter-Thiebaut, and Megane Denu

Subjects
medicine.medical_specialty, Lung, business.industry, Hemodynamics, Hypoxia (medical), medicine.disease, Pulmonary hypertension, Endocrinology, medicine.anatomical_structure, Ventricle, Erythropoietin, hemic and lymphatic diseases, Internal medicine, medicine.artery, Pulmonary artery, medicine, Ventricular pressure, medicine.symptom, business, medicine.drug
Abstract

Background: Pulmonary hypertension (PH) is characterized by increased pulmonary vascular resistance leading to right ventricular failure. Chronic hypoxia is a risk factor for PH. Otherwise, end-stage renal disease treated by haemodialysis is a risk factor for PH that occurs in 40% of the patients. Most of these last patients are treated with human recombinant erythropoietin (EPO) because of anaemia. Involvement of EPO itself as causative agent of PH is a controversial issue. Aims: We investigated if EPO could by itself recapitulate all hemodynamic and morphologic features of hypoxia-induced pulmonary hypertension at similar level of increased haematocrit. As a secondary endpoint, we investigated whether endothelial progenitor cells, mobilized and implied in PH due to chronic hypoxia, could also be involved in EPO-induced PH. Methods: 1 st group: mice were treated with recombinant human EPO in normoxia during 2 weeks. 2 nd group: mice were exposed to 2 weeks of hypoxia (10%). Control mice were placed in normoxic conditions. Blood analysis, echocardiography, right ventricular pressure, heart and lung histology and blood circulating endothelial progenitor cells were assessed after 2 weeks. Results: 2 weeks exogenous EPO treatment causes PH with an important increase in pulmonary and right ventricular pressure but without inducing right ventricle hypertrophy and pulmonary artery remodelling. EPO provoked an increase in the blood mobilization of endothelial progenitor cells at a similar extent than hypoxia. Conclusions: EPO recapitulates hemodynamic features of hypoxia-induced pulmonary hypertension in mice. Similarly to this last disease, EPO mobilizes cells that trigger PH.

Published
2016
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12. Human and mouse essentiality screens as a resource for disease gene discovery

Author

Cacheiro, Pilar, Muñoz-Fuentes, Violeta, Westerberg, Henrik, Scott, R. H., Siddiq, A., Sieghart, A., Smith, K. R., Sosinsky, A., Spooner, W., Stevens, H. E., Stuckey, A., Sultana, R., Thomas, E. R. A., Konopka, Tomasz, Thompson, S. R., Tregidgo, C., Tucci, A., Walsh, E., Watters, S. A., Welland, M. J., Williams, E., Witkowska, K., Wood, S. M., Zarowiecki, M., Hsu, Chih-Wei, Marschall, Susan, Lengger, Christoph, Maier, Holger, Seisenberger, Claudia, Bürger, Antje, Kühn, Ralf, Schick, Joel, Hörlein, Andreas, Oritz, Oskar, Giesert, Florian, Christiansen, Audrey, Beig, Joachim, Kenyon, Janet, Codner, Gemma, Fray, Martin, Johnson, Sara J, Cleak, James, Szoke-Kovacs, Zsombor, Lafont, David, Vancollie, Valerie E, McLaren, Robbie S B, Lanza, Denise G, Hughes-Hallett, Lena, Rowley, Christine, Sanderson, Emma, Galli, Antonella, Tuck, Elizabeth, Green, Angela, Tudor, Catherine, Siragher, Emma, Dabrowska, Monika, Mazzeo, Cecilia Icoresi, Beaudet, Arthur L, Griffiths, Mark, Gannon, David, Doe, Brendan, Cockle, Nicola, Kirton, Andrea, Bottomley, Joanna, Ingle, Catherine, Ryder, Edward, Gleeson, Diane, Ramirez-Solis, Ramiro, Heaney, Jason D, Birling, Marie-Christine, Pavlovic, Guillaume, Ayadi, Abdel, Hamid, Meziane, About, Ghina Bou, Champy, Marie-France, Jacobs, Hugues, Wendling, Olivia, Leblanc, Sophie, Vasseur, Laurent, Fuchs, Helmut, Chesler, Elissa J, Kumar, Vivek, White, Jacqueline K, Svenson, Karen L, Wiegand, Jean-Paul, Anderson, Laura L, Wilcox, Troy, Clark, James, Ryan, Jennifer, Denegre, James, Gailus-Durner, Valerie, Stearns, Tim, Philip, Vivek, Witmeyer, Catherine, Bates, Lindsay, Seavey, Zachary, Stanley, Pamela, Willet, Amelia, Roper, Willson, Creed, Julie, Moore, Michayla, Sorg, Tania, Dorr, Alex, Fraungruber, Pamelia, Presby, Rose, Mckay, Matthew, Nguyen-Bresinsky, Dong, Goodwin, Leslie, Urban, Rachel, Kane, Coleen, Murray, Stephen A, Prochazka, Jan, Novosadova, Vendula, Lelliott, Christopher J, Wardle-Jones, Hannah, Wells, Sara, Teboul, Lydia, Cater, Heather, Stewart, Michelle, Hough, Tertius, Wurst, Wolfgang, Dickinson, Mary E, Sedlacek, Radislav, Adams, David J, Seavitt, John R, Tocchini-Valentini, Glauco, Mammano, Fabio, Braun, Robert E, McKerlie, Colin, Herault, Yann, de Angelis, Martin Hrabě, Mallon, Ann-Marie, Bucan, Maja, Lloyd, K C Kent, Brown, Steve D M, Parkinson, Helen, Meehan, Terrence F, Smedley, Damian, Consortium, Genomics England Research, Consortium, International Mouse Phenotyping, Ambrose, J. C., Arumugam, P., Baple, E. L., Nutter, Lauryl M J, Bleda, M., Boardman-Pretty, F., Boissiere, J. M., Boustred, C. R., Brittain, H., Caulfield, M. J., Chan, G. C., Craig, C. E. H., Daugherty, L. C., de Burca, A., Peterson, Kevin A, Devereau, A., Elgar, G., Foulger, R. E., Fowler, T., Furió-Tarí, P., Hackett, J. M., Halai, D., Hamblin, A., Henderson, S., Holman, J. E., Haselimashhadi, Hamed, Hubbard, T. J. P., Ibáñez, K., Jackson, R., Jones, L. J., Kasperaviciute, D., Kayikci, M., Lahnstein, L., Lawson, K., Leigh, S. E. A., Leong, I. U. S., Flenniken, Ann M, Lopez, F. J., Maleady-Crowe, F., Mason, J., McDonagh, E. M., Moutsianas, L., Mueller, M., Murugaesu, N., Need, A. C., Odhams, C. A., Patch, C., Morgan, Hugh, Perez-Gil, D., Polychronopoulos, D., Pullinger, J., Rahim, T., Rendon, A., Riesgo-Ferreiro, P., Rogers, T., Ryten, M., Savage, K., Sawant, K., Cacheiro, Pilar [0000-0002-6335-8208], Muñoz-Fuentes, Violeta [0000-0003-3574-546X], Nutter, Lauryl MJ [0000-0001-9619-146X], Peterson, Kevin A [0000-0001-8353-3694], Haselimashhadi, Hamed [0000-0001-7334-2421], Konopka, Tomasz [0000-0003-3042-4712], Hsu, Chih-Wei [0000-0002-9591-9567], Lanza, Denise G [0000-0001-8750-6933], Heaney, Jason D [0000-0001-8475-8828], Fuchs, Helmut [0000-0002-5143-2677], Gailus-Durner, Valerie [0000-0002-6076-0111], Lelliott, Christopher J [0000-0001-8087-4530], Adams, David J [0000-0001-9490-0306], Mammano, Fabio [0000-0003-3751-1691], McKerlie, Colin [0000-0002-2232-0967], Herault, Yann [0000-0001-7049-6900], de Angelis, Martin Hrabě [0000-0002-7898-2353], Lloyd, KC Kent [0000-0002-5318-4144], Smedley, Damian [0000-0002-5836-9850], Apollo - University of Cambridge Repository, Queen Mary University of London (QMUL), European Bioinformatics Institute [Hinxton] (EMBL-EBI), EMBL Heidelberg, The Jackson Laboratory [Bar Harbor] (JAX), Baylor College of Medicine (BCM), Baylor University, University of Pennsylvania, The Hospital for sick children [Toronto] (SickKids), Mount Sinai Hospital [Toronto, Canada] (MSH), MRC Harwell Institute [UK], Helmholtz Zentrum München = German Research Center for Environmental Health, Institut Clinique de la Souris (ICS), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), French National Infrastructure for Mouse Phenogenomics (PHENOMIN), Institute of Molecular Genetics of the Czech Academy of Sciences (IMG / CAS), Czech Academy of Sciences [Prague] (CAS), The Wellcome Trust Sanger Institute [Cambridge], Technische Universität München = Technical University of Munich (TUM), Ludwig-Maximilians-Universität München (LMU), CNR - Italian National Research Council (CNR), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), German Center for Diabetes Research - Deutsches Zentrum für Diabetesforschung [Neuherberg] (DZD), University of California [Davis] (UC Davis), University of California (UC), J C Ambrose, P Arumugam, E L Baple, M Bleda, F Boardman-Pretty, J M Boissiere, C R Boustred, H Brittain, M J Caulfield, G C Chan, C E H Craig, L C Daugherty, A de Burca, A Devereau, G Elgar, R E Foulger, T Fowler, P Furió-Tarí, J M Hackett, D Halai, A Hamblin, S Henderson, J E Holman, T J P Hubbard, K Ibáñez, R Jackson, L J Jones, D Kasperaviciute, M Kayikci, L Lahnstein, K Lawson, S E A Leigh, I U S Leong, F J Lopez, F Maleady-Crowe, J Mason, E M McDonagh, L Moutsianas, M Mueller, N Murugaesu, A C Need, C A Odhams, C Patch, D Perez-Gil, D Polychronopoulos, J Pullinger, T Rahim, A Rendon, P Riesgo-Ferreiro, T Rogers, M Ryten, K Savage, K Sawant, R H Scott, A Siddiq, A Sieghart, K R Smith, A Sosinsky, W Spooner, H E Stevens, A Stuckey, R Sultana, E R A Thomas, S R Thompson, C Tregidgo, A Tucci, E Walsh, S A Watters, M J Welland, E Williams, K Witkowska, S M Wood, M Zarowiecki, Susan Marschall, Christoph Lengger, Holger Maier, Claudia Seisenberger, Antje Bürger, Ralf Kühn, Joel Schick, Andreas Hörlein, Oskar Oritz, Florian Giesert, Joachim Beig, Janet Kenyon, Gemma Codner, Martin Fray, Sara J Johnson, James Cleak, Zsombor Szoke-Kovacs, David Lafont, Valerie E Vancollie, Robbie S B McLaren, Lena Hughes-Hallett, Christine Rowley, Emma Sanderson, Antonella Galli, Elizabeth Tuck, Angela Green, Catherine Tudor, Emma Siragher, Monika Dabrowska, Cecilia Icoresi Mazzeo, Mark Griffiths, David Gannon, Brendan Doe, Nicola Cockle, Andrea Kirton, Joanna Bottomley, Catherine Ingle, Edward Ryder, Diane Gleeson, Ramiro Ramirez-Solis, Marie-Christine Birling, Guillaume Pavlovic, Abdel Ayadi, Meziane Hamid, Ghina Bou About, Marie-France Champy, Hugues Jacobs, Olivia Wendling, Sophie Leblanc, Laurent Vasseur, Elissa J Chesler, Vivek Kumar, Jacqueline K White, Karen L Svenson, Jean-Paul Wiegand, Laura L Anderson, Troy Wilcox, James Clark, Jennifer Ryan, James Denegre, Tim Stearns, Vivek Philip, Catherine Witmeyer, Lindsay Bates, Zachary Seavey, Pamela Stanley, Amelia Willet, Willson Roper, Julie Creed, Michayla Moore, Alex Dorr, Pamelia Fraungruber, Rose Presby, Matthew Mckay, Dong Nguyen-Bresinsky, Leslie Goodwin, Rachel Urban, Coleen Kane, Herault, Yann, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)

Subjects
0301 basic medicine, Mutation rate, Cancer Research, [SDV]Life Sciences [q-bio], General Physics and Astronomy, methods [Genetic Association Studies], Disease, VARIANTS, Mice, Essential, 0302 clinical medicine, IMPC, Genetics research, Lethal allele, 2.1 Biological and endogenous factors, Aetiology, lcsh:Science, Organism, ComputingMilieux_MISCELLANEOUS, Disease gene, Mice, Knockout, 0303 health sciences, Multidisciplinary, Genes, Essential, genetics [Disease], Genomics, R/BIOCONDUCTOR PACKAGE, DATABASE, UPDATE, GENOME, [SDV] Life Sciences [q-bio], Knockout mouse, Identification (biology), ddc:500, International Mouse Phenotyping Consortium, Technology Platforms, Biotechnology, Knockout, Science, Computational biology, Biology, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Genetics, medicine, Animals, Humans, Genetic variation, Clinical genetics, Gene, Genetic Association Studies, 030304 developmental biology, Disease model, Prevention, Human Genome, General Chemistry, medicine.disease, Developmental disorder, Good Health and Well Being, 030104 developmental biology, Genomics England Research Consortium, Genes, lcsh:Q, Generic health relevance, 030217 neurology & neurosurgery, Rare disease
Abstract

The identification of causal variants in sequencing studies remains a considerable challenge that can be partially addressed by new gene-specific knowledge. Here, we integrate measures of how essential a gene is to supporting life, as inferred from viability and phenotyping screens performed on knockout mice by the International Mouse Phenotyping Consortium and essentiality screens carried out on human cell lines. We propose a cross-species gene classification across the Full Spectrum of Intolerance to Loss-of-function (FUSIL) and demonstrate that genes in five mutually exclusive FUSIL categories have differing biological properties. Most notably, Mendelian disease genes, particularly those associated with developmental disorders, are highly overrepresented among genes non-essential for cell survival but required for organism development. After screening developmental disorder cases from three independent disease sequencing consortia, we identify potentially pathogenic variants in genes not previously associated with rare diseases. We therefore propose FUSIL as an efficient approach for disease gene discovery., Discovery of causal variants for monogenic disorders has been facilitated by whole exome and genome sequencing, but does not provide a diagnosis for all patients. Here, the authors propose a Full Spectrum of Intolerance to Loss-of-Function (FUSIL) categorization that integrates gene essentiality information to aid disease gene discovery.

Published
2020
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