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In vivo gene therapy in a murine model of injury, from a lentiviral vector carrying the soluble TGF²-1 receptor, aiming at reducing skeletal muscle fibrosis during muscle repair.

Grant number: 22/07471-8
Support Opportunities:Scholarships in Brazil - Master
Effective date (Start): November 01, 2022
Status:Discontinued
Field of knowledge:Biological Sciences - Genetics - Human and Medical Genetics
Principal Investigator:Roberta Sessa Stilhano Yamaguchi
Grantee:Luana de Mambro
Host Institution: Faculdade de Ciências Médicas da Santa Casa de São Paulo (FCMSCSP). Fundação Arnaldo Vieira de Carvalho. São Paulo , SP, Brazil
Associated scholarship(s):23/17660-5 - Cell-free therapy: biomaterial-based delivery of engineered mesenchymal stem cells extracellular vesicles (MSCs-EVs) to enhance skeletal muscle repair and reduce fibrosis., BE.EP.MS

Abstract

Muscle injuries can be caused by lacerations, strains or bruises, the latter two being responsible for more than 90% of all traumas caused in sports. In the case of more extensive injuries, in which volumetric muscle loss (LMCV) occurs, the physiological repair mechanism is overloaded, favoring dysfunctional tissue repair, with the formation of exacerbated fibrotic tissue, mainly by the release of TGF²1. It occurs because this cytokine binds to the type II receptor (T²RII) on the sarcolemma membrane and activates signaling pathways that lead to decreased expression of mitotic genes and increased expression of fibrotic and atrophic genes. Thus, the search for treatments that seek to categorically reverse the exacerbation of this fibrotic mechanism has been of great value, with Gene Therapy (GT) being one of the most studied techniques today. Thus, the work presents a TG-based system, in which the lentiviral vector Lv-pNF-kB-sT²RII will be constructed, aiming to reduce fibrosis in a murine model of muscle injury by contusion, by inhibiting TGF²-1 from the inducible promoter NF-kB. The project will be divided into two main strands, the first being characterized by the evaluation of the in vitro functionality of the vector, including the construction of lentivetors and analysis of their activity in C2CC12 cells from the expression of NF-kB, induced by cardiotoxin, and the second aspect will be the performance of gene therapy in vivo, from murine models of lesion, which will receive the vector and will be evaluated by Rota-Rod test, histology and immunohistochemistry. The data obtained will be gathered for statistical analysis in the GraphPad Prism 8 program. Thus, it is expected with these results, to obtain a reduction in muscle fibrosis, an increase in tissue regeneration and functional recovery of skeletal muscle.

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