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Title Disferlinopatías: nuevos aspectos diagnósticos y terapéuticos
Publication Date
Date Accessioned
Discipline/Department Departament de Medicina
University/Publisher Universitat Autònoma de Barcelona
Abstract Dysferlin is a protein expressed in the skeletal muscle. Despite its function is not completely known yet, it seems that participate in the process of membrane reparation after a damage. Patients with mutation in the dysferlin gene develop a muscle dystrophy characterized by a progressive weakness of the muscles of the lower and upper limbs. There is not any effective treatment for this disease yet. In the present thesis we have studied diagnostic and therapeutics aspects of the disease. We have demonstrated that the study of the expression of dysferlin in monocytes from peripheral blood is useful to detect patients with dysferlinopathy. This technique is quick, a result can be obtained in less tan 48 hours, as avoid the need of a muscle biopsy in patients affected. Moreover, it allows the study of mutations in the dysferlin gene. There are different patterns of expression of dysferlin related to the number of mutation present in the gene. In patients with two mutations, levels are between 0 and 20%. In carriers of one mutation in the gene, levels of expression are between 20 and 80% and finally in patients with no mutation in the dysferlin gene, levels are higher than 80%. We have also demonstrated that there is a good correlation between the expression of dysferlin in monocytes and in skeletal muscle. For this reason, we think that the study of dysferlin expression in monocytes could be a good tool to follow-up patients treated with drugs able to increase the expression of dysferlin. From a therapeutic point of view we have investigated two different options. We have demonstrated that vitamin D is able to increase the expression of dysferlin both in monocytes and in myotubes of carriers of a single mutation in the dysferlin gene in vitro. These results have been confirmed in vivo trough a clinical trial where healthy carriers of a single mutation in the dysferlin gene have been treated with vitamin D. We have also demonstrated that transplantation of mesoangioblasts (MABs), a mesenchymal stem cell, is effective in a murine model of the disease. MABs were isolated from muscle biopsies of adult healthy mice and injected into the femoral artery of A/J SCID mice. The cells were able to colonize the skeletal muscle, fusing with the regenerating muscle fibres and restoring the expression of dysferlin. Moreover, we demonstrated that this new dysferlin was completely functional, because muscle fibres treated were able to repair the membrane after an external damage. In view that MABs are a subtype of pericytes, periendothelial cells present in the normal skeletal muscle, we wondered if these cells are able to participate in the normal process of muscle regeneration. We observed that the population of pericytes is increased in dystrophic muscle biopsies of our patients. There was a good correlation between the degree of muscle regeneration and degeneration an the number of pericytes in the biopsy. We have observed that pericytes expressed transcription factors specific of skeletal muscle differentiation pathway in…
Subjects/Keywords Disferlina; Fistrofia muscular; Células madre; Ciències de la Salut; 616.8
Contributors [email protected] (authoremail); true (authoremailshow); Illa Sendra, Isabel (director); true (authorsendemail)
Language es
Rights ADVERTIMENT. L'accés als continguts d'aquesta tesi doctoral i la seva utilització ha de respectar els drets de la persona autora. Pot ser utilitzada per a consulta o estudi personal, així com en activitats o materials d'investigació i docència en els termes establerts a l'art. 32 del Text Refós de la Llei de Propietat Intel·lectual (RDL 1/1996). Per altres utilitzacions es requereix l'autorització prèvia i expressa de la persona autora. En qualsevol cas, en la utilització dels seus continguts caldrà indicar de forma clara el nom i cognoms de la persona autora i el títol de la tesi doctoral. No s'autoritza la seva reproducció o altres formes d'explotació efectuades amb finalitats de lucre ni la seva comunicació pública des d'un lloc aliè al servei TDX. Tampoc s'autoritza la presentació del seu contingut en una finestra o marc aliè a TDX (framing). Aquesta reserva de drets afecta tant als continguts de la tesi com als seus resums i índexs.
Country of Publication es
Record ID handle:10803/116077
Repository barcelona
Date Indexed 2019-12-30
Issued Date 2013-02-22 00:00:00

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