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Our project is to determine the potential contribution of diseased astrocytes in the upregulation of CRMP4 in resistant MNs in order to develop therapeutic approaches based on CRMP4 downregulation on SOD1G93A mice. By using an astrocyte-motoneuron coculture system, we observed a significant increase in CRMP4 specifically in SOD1G93A MNs plated on SOD1G93A astrocytes or treated with culture medium conditioned by SOD1G93A astrocytes. In vivo, the silencing of mutated SOD1 expression specifically in astrocytes, abolished the increase in CRMP4 level previously observed in SOD1G93A MNs at the onset of symptoms. Using the immunodetection of Matrix Metallopeptidase 9 (MMP9) and retrograde labeling experiments, we demonsrated that the increase in CRMP4 expression occurred mainly in the RES populations of SOD1G93A MNs. All these results demonstrate for the first time the cooperation between glial cells and motoneurons in the selective degeneration of the resistant motoneurons, and may encourage the development of new strategies based on CRMP4 reduction for ALS. (1) Saxena S, Nat Neurosci ,2009 (2) Dirren E, Ann Clin Transl Neurol, 2015 (3) Duplan L, J. Neurosci, 2010 crmp4, astrocytes, motoneuron degeneration P03- Animal models- N° 27 to N° 49 Animal models- #2457 P03- 27- Dystrophin deficient rats: A robust animal model for duchenne muscular dystrophy studies Aude LAFOUX (1), Thibaut LARCHER (2), Laurent TESSON (3), Severine REMY (3), Virginie THEPENIER (3), Caroline Le GUINER (4), Virginie FRANCOIS (4), Lydie GUIGAND (2), Gilles TOUMANIANTZ (1), Anne De Cian (5), Charlotte BOIX (5), Jean-Baptiste RENAUD (5), Yan CHEREL (2), Carine GIOVANNANGELI (5), Jean-Paul CONCORDET (5), Ignacio ANEGON (3), Corinne HUCHET (1) 1. INSERM U1087, Université Nantes, Nantes, France 2. INRA UMR 703 , ONIRIS, Nantes, France 3. INSERM U1064, Université Nantes, Nantes, France 4. Atlantic Gene Therapies, INSERM U1089 , Université Nantes, Nantes, France 5. INSERM U1154 , Museum National Histoire Naturelle, Paris, France Duchenne Muscular Dystrophy (DMD) is a severe muscle-wasting disorder caused by mutations in the dystrophin gene, without curative treatment yet available. For pre-clinical evaluation of therapeutic approaches, few animal models are available. Large animal models of DMD such as dogs or pigs are expensive, difficult to handle and show important clinical heterogeneity, while mdx mice exhibit only limited chronic muscular lesions and muscle weakness. A rat model could represent a useful alternative since rats are small animals but 10 times bigger than mice and could better mimic the human disease. A line of Dmd mutated-rats (Dmdmdx) was generated using TALENs. Animals showed undetectable levels of dystrophin by western-blot and less than 5 % of dystrophin positive fibers by immunohistochemistry in muscles analyzed. The results showed that Dmdmdx rats have significantly reduced body weight from 4 weeks. At 3 months, limb and diaphragm muscles displayed intense necrosis and regeneration. At 7 and 12 months, these muscles showed severe fibrosis and adipose tissue infiltration. From 6 weeks, Dmdmdx rats showed significant reduction in muscle strength associated with muscular fatigue and a decrease in spontaneous motor activity. Concerning the heart, echocardiography showed significant concentric remodeling and alteration of diastolic function at 3 months. Subsequently, the heart morphology evolved into a dilated cardiomyopathy with necrotic and fibrotic tissue. A long-term study showed that life span was reduced in Dmdmdx rats. Furthermore, cardiac insufficiency or dilated cardiomyopathy were frequently the direct cause of death of these Dmdmdx rats. In conclusion, Dmdmdx rats represent a very promising small animal model that can be used now for pre-clinical evaluation of therapeutic approaches of DMD, in particular for testing effects on disease progression and cardiac anomalies that were difficult to assess using the current DMD animal models. animal model, muscular dystrophy, skeletal muscle, heart, TALENs Animal models- #2526 P03- 28- Characterization of a DmdEGFP reporter mouse Mina V. Petkova (1), Susanne Morales-Gonzales (1), Esther Gill (1), Franziska Seifert (1), Josefine Radke (2), Werner Stenzel (2), Luis Garcia (3), Helge Amthor (3), Markus Schuelke (1) 1. NeuroCure Clinical Research Center, Charité?Universitätsmedizin, Berlin, Allemagne 2. Department of Neuropathology, Charité?Universitätsmedizin, Berlin, Allemagne 3. INSERM U1179 and LIA BAHN Centre scientifique de Monaco, Montigny-le Bretonneux, Université de Versailles St-Quentin, Saint-Quentin-en-Yvelines, France We generated a novel DmdEGFP reporter mouse, in which an EGFP coding sequence was inserted behind exon 79 of the Dmd gene. This exon is known to be present in most dystrophin isoforms and splice variants, as well as in revertant dystrophin. To date no dystrophin reporter mice exist and imaging is only possible by indirect antibody-mediated staining ex-vivo. We characterized this mouse model and found by Western blot analysis normal dystrophin expression levels in limb muscles, diaphragm, heart, brain, and retina. We found high native EGFP fluorescence at all expected sites of dystrophin expression. Skeletal muscles showed normal histology as well as sarcolemmal/subsarcolemmal localization of dystrophin-EGFP and of Page 37 components of the dystrophin associated protein complex. These findings rule out a dystrophic phenotype that might have been introduced by the C-terminal EGFP-tag. Following the EGFP fluorescence under the microscope it is easy to distinguish between muscles from reporter mice and their wildtype littermates, even on the level of single isolated muscle fibers. The novel dystrophin reporter mouse provides a valuable tool for direct visualization of dystrophin expression. Animal models- #2530 P03- 29- Importance of alum particle size for delayed neurotoxic effects of intramuscular injections in CD1 mice. Guillemette Crepeaux (1), Housam Eidi (2), Eleni Tzavara (3), Jessie Aouizerate (1), Marie-Odile David (4), Bruno Giros (3), Christopher Exley (5), Christopher Shaw (6), François-Jérome Authier (1), Josette Cadusseau (1), Romain Gherardi (1) 1. BNMS, IMRB, creteil, France 2. BNMS, IMRB, creteil, 3. UPMC UM CR18, UPMC, Paris, France 4. Inserm U1204, University of Evry, Evry, France 5. Keele University, Keele University, Staffordshire, Royaume Uni 6. University of British Columbia, University of British Columbia, Vancouver, Canada Vaccines have allowed the eradication or containment of several severe infectious diseases. Adjuvants such as aluminium hydroxide particles (alum) have long been added to vaccines to initiate and enhance the immune response. Concerns linked to the use of alum particles emerged following recognition of their unexpectedly long-lasting biopersistence within immune cells of patients with chronic fatigue, cognitive dysfunction, myalgias and autoimmune/inflammatory features. Previous experimental reports have documented slow translocation of alum particles from the injected muscle to brain. The present study aimed at evaluating mouse behaviour and Al cerebral concentrations long after intramuscular injections of various doses of alum. Alum adjuvant particles (Alhydrogel®) were injected in the tibialis anterior muscle in adult female CD1 mice at different doses ranging from 133 to 800 µg Al/kg of body weight. Eight validated tests were performed to evaluate behaviour and motor performances 180 days after injection. Brains removed after test session allowed determination of Al levels by atomic furnace absorption spectrometry. A very unusual neuro-toxicological pattern limited to lower doses of alum was observed. Neurobehavioural changes, including decreased activity levels and depressed adaptative anxiety-like behaviour, were documented in animals exposed to the two lowest doses (133 and 200 µg Al/kg) but not at the highest dose (800 µg Al/kg), compared to controls. Consistently, cerebral Al levels were increased in animals exposed to the lowest doses. This study shows that, depending on the experimental conditions, alum particles injected in muscle may induce neurotoxic effects and Al cerebral accumulation several months after injection. Above all, it appears that particle properties, such as agglomeration and particle size, are critical parameters influencing their toxicity. Indeed in vivo neurotoxic effects are presently restricted to smaller particles and lower doses, showing non-monotonic ?U? dose-response curves. In contrast to common belief that increasing the dose makes the poison, futures studies on potential toxic effects of aluminum-based adjuvants should specifically focus on small-size or low-dose conditions. Al hydroxyde, vaccine, MMF, neurotoxicity, behaviour, mice, non-monotonic dose response Animal models- #2578 P03- 30- Inflammation, muscular loss and ubiquitin ligases up-regulation: a new murine model of septic cachexia Damien Restagno (1), Ludovic Freyburger (1), Christian Paquet (1), Jeanne-Marie Bonnet (1), Vanessa Louzier (1) 1. APCSE Agressions Pulmonaires et Circulatoires dans le Sepsis, VetAgro Sup, Marcy l'Etoile, France Background Severe injury and sepsis are associated with metabolic changes as catabolic response in skeletal muscle and result in muscle atrophy. Massive inflammation as occurring during sepsis contributes to weight and muscular loss. Indeed, expression of pro- inflammatory cytokines such as TNF? and IL-6 in the early phase of sepsis is known to trigger cachexia. Pro-inflammatory cytokines
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    GUIDELINE Genetic Testing Guidelines Categories This Guideline Applies To: Clinical Care Management CM, TCHP Texas Children's Health Plan Guidelines, Utilization Management UM Guideline # 6181 Document Owner Bhavana Babber GUIDELINE STATEMENT: Texas Children's Health Plan (TCHP) performs authorization of genetic testing requests. PRIOR AUTHORIZATION GUIDELINES 1. Genetic testing conducted by out-of-network providers will be treated as out-of-network requests and will comply with the out-of-network authorization Guidelines. 2. Requests for Noninvasive Prenatal Testing will comply with TCHP Noninvasive Prenatal Testing Guidelines. 3. All requests for prior authorization for genetic testing are received via fax, phone or mail by the Utilization Management Department and processed during normal business hours. 4. The Utilization Management professional receiving the request evaluates the submitted information to determine if the documentation supports the genetic testing as an eligible service. 5. To request prior authorization for genetic testing, documentation supporting the medical necessity of the test requested must be provided. 6. TCHP will apply clinical criteria in the current Texas Medicaid Provider Manual (TMPPM) at the time of the request when applicable for the following: 6.1.BRCA gene mutation analysis 6.2.Genetic Testing for colorectal cancer 6.3.Cytogenetic testing 6.4.Pharmacogenetic Testing Version #: 5 Genetic Testing Guidelines Page 1 of 10 Printed copies are for reference only. Please refer to the electronic copy for the latest version. GUIDELINE 6.5. A request for retroactive authorization must be submitted no later than seven calendar days beginning the day after the lab draw is performed per TMPPM 7. Whole genome sequencing (code 81415) requires preauthorization on a case-by-case basis.
  • Post-Transcriptional Regulation of Hfe Gene Expression

    Post-Transcriptional Regulation of Hfe Gene Expression

    RUTE ISABEL PAULO MARTINS POST-TRANSCRIPTIONAL REGULATION OF HFE GENE EXPRESSION LISBOA 2010 nº de arquivo “copyright” RUTE ISABEL PAULO MARTINS POST-TRANSCRIPTIONAL REGULATION OF HFE GENE EXPRESSION Thesis presented to obtain the Ph.D. degree in Biology (Molecular Genetics), by the Universidade Nova de Lisboa, Faculdade de Ciências e Tecnologia. LISBOA 2010 Agradecimentos Agradecimentos Ao concluir este trabalho gostaria de expressar o meu reconhecimento a todos aqueles que de algum modo contribuíram para a sua concretização. Esta tese de Doutoramento é o resultado de um trabalho de investigação realizado no Departamento de Genética do Instituto Nacional de Saúde Dr. Ricardo Jorge (INSA), em Lisboa, entre Janeiro de 2006 a Dezembro de 2009, onde foram disponibilizadas as condições essenciais para o seu desenvolvimento. Ao Presidente do Conselho Directivo do INSA, Professor Doutor José Pereira Miguel, manifesto o meu apreço. Agradeço à Doutora Maria Guida Boavida e ao Doutor João Lavinha por me terem recebido no então Centro de Genética Humana, permitindo a realização do meu trabalho, e por todo o interesse que demonstraram pelo mesmo. Este trabalho foi, na sua maioria, financiado pela Fundação para a Ciência e a Tecnologia no âmbito do projecto de investigação PTDC/SAU/GMG/64494/2006, através do Programa de Financiamento Plurianual do Centro de Investigação em Genética Molecular Humana e sob a forma de uma Bolsa de Doutoramento com a referência SFRH/BD/21340/2005. À minha orientadora Doutora Paula Faustino estou reconhecida pela oportunidade inicial de me integrar no seu grupo de investigação, cujo acompanhamento ao longo destes oito anos tem sido crucial para a minha formação enquanto cientista.
  • Characterization of the Dysferlin Protein and Its Binding Partners Reveals Rational Design for Therapeutic Strategies for the Treatment of Dysferlinopathies

    Characterization of the Dysferlin Protein and Its Binding Partners Reveals Rational Design for Therapeutic Strategies for the Treatment of Dysferlinopathies

    Characterization of the dysferlin protein and its binding partners reveals rational design for therapeutic strategies for the treatment of dysferlinopathies Inauguraldissertation zur Erlangung der Würde eines Doktors der Philosophie vorgelegt der Philosophisch-Naturwissenschaftlichen Fakultät der Universität Basel von Sabrina Di Fulvio von Montreal (CAN) Basel, 2013 Genehmigt von der Philosophisch-Naturwissenschaftlichen Fakultät auf Antrag von Prof. Dr. Michael Sinnreich Prof. Dr. Martin Spiess Prof. Dr. Markus Rüegg Basel, den 17. SeptemBer 2013 ___________________________________ Prof. Dr. Jörg SchiBler Dekan Acknowledgements I would like to express my gratitude to Professor Michael Sinnreich for giving me the opportunity to work on this exciting project in his lab, for his continuous support and guidance, for sharing his enthusiasm for science and for many stimulating conversations. Many thanks to Professors Martin Spiess and Markus Rüegg for their critical feedback, guidance and helpful discussions. Special thanks go to Dr Bilal Azakir for his guidance and mentorship throughout this thesis, for providing his experience, advice and support. I would also like to express my gratitude towards past and present laB members for creating a stimulating and enjoyaBle work environment, for sharing their support, discussions, technical experiences and for many great laughs: Dr Jon Ashley, Dr Bilal Azakir, Marielle Brockhoff, Dr Perrine Castets, Beat Erne, Ruben Herrendorff, Frances Kern, Dr Jochen Kinter, Dr Maddalena Lino, Dr San Pun and Dr Tatiana Wiktorowitz. A special thank you to Dr Tatiana Wiktorowicz, Dr Perrine Castets, Katherine Starr and Professor Michael Sinnreich for their untiring help during the writing of this thesis. Many thanks to all the professors, researchers, students and employees of the Pharmazentrum and Biozentrum, notaBly those of the seventh floor, and of the DBM for their willingness to impart their knowledge, ideas and technical expertise.