Assessing the ability of LARGE overexpression to prevent the development of muscular dystrophy
Duchenne Muscular Dystrophy (DMD) is a hereditary X-linked fatal disease that affects 1 in 3500 male births. It is the most common kind of muscular dystrophy in children and leads to death in the late teens or early 20s for many patients. The mdx mouse is a model of DMD that can be used to investiga...
| Autor principal: | |
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| Formato: | Second cycle, A2E |
| Lenguaje: | sueco Inglés |
| Publicado: |
2014
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| Materias: | |
| Acceso en línea: | https://stud.epsilon.slu.se/6617/ |
| _version_ | 1855571043714859008 |
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| author | Rudberg, Astrid |
| author_browse | Rudberg, Astrid |
| author_facet | Rudberg, Astrid |
| author_sort | Rudberg, Astrid |
| collection | Epsilon Archive for Student Projects |
| description | Duchenne Muscular Dystrophy (DMD) is a hereditary X-linked fatal disease that affects 1 in 3500 male births. It is the most common kind of muscular dystrophy in children and leads to death in the late teens or early 20s for many patients. The mdx mouse is a model of DMD that can be used to investigate experimental therapies. Overexpression of a glycosyltransferase, CT GalNAc, in mdx mice has been demonstrated to prevent the development of muscular dystrophy. Overexpression of another glycosyltransferase, LARGE, is currently being investigated as a treatment for another group of muscular dystrophies, the dystroglycanopathies.
In this study, we overexpressed LARGE in mdx mice in order to investigate its effect on the development of muscular dystrophy. We found that the transgene was expressed in our LV5/mdx mice, as seen with both immunohistochemistry and western blots, but that overexpressing the enzyme unfortunately appeared to have a negative effect on the dystrophy. An increase in pathology was seen histologically at both 3 and 8 weeks of age in the LV5/mdx mice when compared to the mdx mice. Physiological measurements on 22 week old mice showed a significantly diminished tolerance to eccentric exercise in the LV5/mdx compared to their mdx littermates. These observations lead us to the conclusion that increased expression of LARGE is not a therapeutic option for DMD patients, but is in fact contraindicated. |
| format | Second cycle, A2E |
| id | RepoSLU6617 |
| institution | Swedish University of Agricultural Sciences |
| language | Swedish Inglés |
| publishDate | 2014 |
| publishDateSort | 2014 |
| record_format | eprints |
| spelling | RepoSLU66172014-09-05T14:47:07Z https://stud.epsilon.slu.se/6617/ Assessing the ability of LARGE overexpression to prevent the development of muscular dystrophy Rudberg, Astrid Animal physiology and biochemistry Animal diseases Duchenne Muscular Dystrophy (DMD) is a hereditary X-linked fatal disease that affects 1 in 3500 male births. It is the most common kind of muscular dystrophy in children and leads to death in the late teens or early 20s for many patients. The mdx mouse is a model of DMD that can be used to investigate experimental therapies. Overexpression of a glycosyltransferase, CT GalNAc, in mdx mice has been demonstrated to prevent the development of muscular dystrophy. Overexpression of another glycosyltransferase, LARGE, is currently being investigated as a treatment for another group of muscular dystrophies, the dystroglycanopathies. In this study, we overexpressed LARGE in mdx mice in order to investigate its effect on the development of muscular dystrophy. We found that the transgene was expressed in our LV5/mdx mice, as seen with both immunohistochemistry and western blots, but that overexpressing the enzyme unfortunately appeared to have a negative effect on the dystrophy. An increase in pathology was seen histologically at both 3 and 8 weeks of age in the LV5/mdx mice when compared to the mdx mice. Physiological measurements on 22 week old mice showed a significantly diminished tolerance to eccentric exercise in the LV5/mdx compared to their mdx littermates. These observations lead us to the conclusion that increased expression of LARGE is not a therapeutic option for DMD patients, but is in fact contraindicated. Duchenne Muskulär Dystrofi (DMD) är en ärftlig X-linkad dödlig sjukdom som drabbar en av 3500 födda pojkar. Det är den vanligaste förekommande typen av muskulär dystrofi hos barn och leder till döden från sena tonår till tidig 20-års ålder för många av de drabbade. mdx-musen är en modell för DMD som kan användas för att utvärdera experimentella behandlingar. Överuttrycket av ett glykosyltransferas, CT GalNAc, hos mdx-musen har visat sig förhindra utvecklingen av muskulär dystrofi. Överuttrycket av ett annat glykosyltransferas, LARGE, undersöks just nu som en möjlig behandling för en annan grupp muskulära dystrofier, dystroglykanopatierna. I den här studien har vi överuttryckt LARGE hos mdx-möss för att kunna undersöka dess effekt på utvecklingen av den muskulära dystrofin. Vi fann att transgenen uttrycktes hos våra LV5/mdx-möss med hjälp av både immunohistokemi och western blot, men att överuttrycket av enzymet tyvärr hade en negativ effekt på utvecklingen av dystrofin. En ökad nivå av patologi kunde ses på histologi gjord hos både 3 och 8 veckor gamla LV5/mdx-möss vid jämförelse med mdx-möss. Fysiologiska mätningar gjorda på 22 veckor gamla möss visade en signifikant minskad tolerans för excentrisk belastning hos LV5/mdx jämfört med deras mdx syskon från samma kull. Dessa iakttagelser fick oss att dra slutsatsen att ett ökat uttryck av LARGE hos DMD-patienter inte är ett alternativ för behandling, utan måste anses kontraindicerat. 2014-04-14 Second cycle, A2E NonPeerReviewed application/pdf sv https://stud.epsilon.slu.se/6617/7/rudberg_a_140905.pdf Rudberg, Astrid, 2014. Assessing the ability of LARGE overexpression to prevent the development of muscular dystrophy. Second cycle, A2E. Uppsala: (VH) > Dept. of Biomedical Sciences and Veterinary Public Health (until 231231) <https://stud.epsilon.slu.se/view/divisions/OID-713.html> urn:nbn:se:slu:epsilon-s-3691 eng |
| spellingShingle | Animal physiology and biochemistry Animal diseases Rudberg, Astrid Assessing the ability of LARGE overexpression to prevent the development of muscular dystrophy |
| title | Assessing the ability of LARGE overexpression to prevent the development of muscular dystrophy |
| title_full | Assessing the ability of LARGE overexpression to prevent the development of muscular dystrophy |
| title_fullStr | Assessing the ability of LARGE overexpression to prevent the development of muscular dystrophy |
| title_full_unstemmed | Assessing the ability of LARGE overexpression to prevent the development of muscular dystrophy |
| title_short | Assessing the ability of LARGE overexpression to prevent the development of muscular dystrophy |
| title_sort | assessing the ability of large overexpression to prevent the development of muscular dystrophy |
| topic | Animal physiology and biochemistry Animal diseases |
| url | https://stud.epsilon.slu.se/6617/ https://stud.epsilon.slu.se/6617/ |