FSHD ANIMAL MODEL. · An animal model to develop therapeutic strategies for facioscapulohumeral muscular dystrophy, FSHD
6РП — Действия „Мария Кюри“
- Период
- 2006-12-01 → 2008-11-30
- Финансиране от ЕС
- 80 000 €
- Участници
- 1
- Схема
- IRG
Линиите свързват координатора с партньорите.
Накратко на български
Молекулярните механизми на лицево-лопаточно-раменната мускулна дистрофия се изследват чрез мишки, които произвеждат прекомерно количество от протеина FRG1. Това помага за разбирането на болестта и тестването на възможни методи за генна терапия.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
Final Activity Report Summary - FSHD ANIMAL MODEL (An Animal Model to Develop Therapeutic Strategies for Facioscapulohumeral Muscular Dystrophy, FSHD.)
The goal of this research project was to understand the molecular mechanism of facioscapulohumeral muscular dystrophy (FSHD) in order to develop possible therapeutic approcahes. FSHD is the third most common muscular dystrophy, for which there is no treatment or cure at present. FSHD is associated with reduction in the number of copies of deoxyribonucleic acid (DNA) on chromosome 4, called D4Z4, which is repeated many times towards the end of the long arm of chromosome 4. We hypothesised that D4Z4 might control the activity of nearby FSHD genes. We found that there was an increased production of the proteins encoded by the genes close to D4Z4 in FSHD patients. Interestingly, we found that these proteins were over-produced, specifically in the muscles of FSHD patients, explaining the fact that FSHD is primarily a disease of skeletal muscle. More recently, through following the idea of modelling in an animal the same conditions observed in FSHD patients, we generated mice that overproduced the same proteins which were overproduced in the muscles of FSHD patients. We found that mice overproducing a protein called FRG1 displayed several features of FSHD patients. Based on these results, we proposed that it was loss of D4Z4 causing overproduction of FRG1, which in turn led to FSHD. During the Marie Curie international reintegration grants (IRG) funding period, we performed the following tasks: 1. we understood the molecular mechanism that was responsible for increased production of 4q35 proteins in FSHD 2. we understood the specific processes that went awry in muscles of patients suffering from FSHD 3. we used the FSHD animal model to test possible gene therapy approaches for FSHD. The results of our research were anticipated to contribute in the development of effective therapeutic approaches for FSHD.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
My primary research interest is to characterize the regulatory pathways controlling muscle-specific gene expression and delineate how they become subverted in disease using Facioscapulohumeral Muscular Dystrophy (FSHD) as a paradigm. FSHD is the third most common myopathy and is characterized by degeneration of selective skeletal muscle groups. FSHD is an autosomal dominant disorder that unlike other neuromuscular diseases it is not linked to a classical mutation within a protein-coding gene. Instead, FSHD patients carry deletions of tandem repeats, termed D4Z4, located on chromosome 4q35. Until recently, an incomplete knowledge of the biochemical pathogenesis of FSHD and lack of an animal model has hampered the development of effective therapies. I found that the 4q35 genes FRG1, FRG2, and ANT1 are inappropriately over-expressed selectively in FSHD skeletal muscle. I identified a silencing element within D4Z4 that contains a binding site for a transcriptional repressing complex. I showed that deletion of this element leads to over-expression of 4q35 genes in FSHD muscle. To identify the gene(s) responsible for FSHD, I generated transgenic mice over-expressing FRG1, FRG2 or ANT1 in muscle. FRG1 mice developed a muscular dystrophy with features characteristic of FSHD whereas FRG2 and ANT1 mice appeared normal. My results also suggest that FRG1 is involved in pre-mRNA splicing. I found that in muscle of FRG1 mice and FSHD patients, specific pre-mRNAs are aberrantly alternatively spliced. I propose that FSHD results from over-expression of FRG1 in muscle, which leads to aberrant splicing of specific pre-mRNAs. My results not only shed new light on the pathogenesis of one of the most important myopathies, but have also provided an interesting model of disease caused by altered chromatin structure and transcription imbalance. This project will generate novel insights into the regulation of muscle-specific gene expression and the molecular pathogenesis of FSHD.""
Оригинален текст от CORDIS (на английски).
Участници
- FONDAZIONE CENTRO SAN RAFFAELE DEL MONTE TABOR · MILANOКоординаторИталия
Връзки
Данни: CORDIS, © Европейски съюз