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Cannabinoid-regulated autophagy as a target for studies involving cytoprotection and maturation of myoblasts obtained from induced pluripotent stem cells

Grant number: 21/14545-5
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): June 01, 2022
Effective date (End): October 31, 2025
Field of knowledge:Biological Sciences - Pharmacology - General Pharmacology
Principal researcher:Claudia Bincoletto Trindade
Grantee:Lucas dos Santos Zamarioli
Home Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil

Abstract

Data in the literature demonstrate that autophagy is involved in the muscle proteolysis process. Recent work carried out by our group in collaboration with the University of Minnesota (under study) has really demonstrated a central role of autophagy in the maturation process of muscle cells obtained from induced pluripotent stem cells. This data is of particular importance, since the process of muscle mass loss is involved in several diseases, including cancer at an advanced stage. Thus, the establishment of in vitro models that can identify drugs that control the muscle proteolysis process is of great scientific interest, as there is a scarcity of data in the literature in this area. Thus, our objective in this project is to continue the project started in 2019 at the University of Minnesota, MN, USA, which involves the cell reprogramming of fibroblasts by the Sendai method, aiming to obtain myogenic progenitors from induced pluripotent stem cells for the in vitro identification of cytoprotective compounds such as cannabinoids (cannabidiol, cannabidivarin and 9-tetrahydrocannabivarin), as there are data in the literature showing a possible cytoprotective effect of these in various cell models through the restoration of autophagy, but few studies are verified with these compounds in models representing skeletal muscle cells. For this, myogenic progenitors subjected to cellular stress with muscle proteolysis inducing agents such as carditoxin, palmitate and conditioned medium of renal nephroma cells will be used in the evaluation of possible cytoprotective effects of cannabinoids via modulation of autophagy. Proteolysis, cell death, signaling proteins, intracellular calcium mobilization, and expression of genes involved in muscle fiber maturation will be performed. In parallel, this project intends to evaluate the in vivo actions of selected compounds in in vitro studies, which will be carried out through the BPE at the University of Minnesota (U of M), MN, USA by administering the selected compounds in mdx animals deficient in dystrophin, which represent a model of Duchene Muscular Dystrophy (DMD) (the description of activities in the U of M is on page 21), as well as the collaboration letter from Dr. Perlingeiro (responsible for the U of M activities). In these animals, after treatment with cannabinoids, we will evaluate the size and number of myofibers, muscle contraction and collagen deposition. Thus, we will have in vitro data on the mechanism of action and its possible action in vivo, which makes the data robust and of great scientific interest in a lacking area regarding licensed drugs to control pathologies/injuries involving the skeletal muscle. (AU)

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