Change Specifically Responses To Mtor Inhibition Based On Brain Of N. Guentheri

Abstract

Torin 2 is a new powerful ATP-competitive inhibitor of two mechanistic target of rapamycin (mTOR) complexes, which are central regulator of growth, proliferation and viability in the cell. This chemical agent was specifically developed and can be verified as potential drug to combat a number of age-related diseases, including cancer, neurodegenerative diseases, cardiomyopathy, sarcopenia, as a more promising alternative to such a well-known substance as rapamycin. Compared to rapamycin and its analogues, Torin 2 has increased bioavailability and an improved pharmacokinetic profile. To improve understanding of the effect of Torin 2 on cellular signaling pathways (including mTOR) and other biological processes, the gene expression changes were estimated in the brain tissues of the annual African killifish Nothobranchius guentheri after prolonged oral administration of Torin 2. Based on the mRNA-seq data, an overrepresentation analysis was performed, including FSEA (Fold-Change-Specific Enrichment Analysis; according to the Gene Ontology database), which, unlike the classical GSEA, narrows down the groups of analysed genes to those that have similar expression changes between the compared groups. Also, in this study, we conducted weighted gene co-expression network analysis (WGCNA) and identified several modules of co-expressed genes, many of which are enriched with participants of key biological processes. Several modules demonstrated predominant differential expression between Torin 2 group and control samples. Our findings may provide a better understanding of the processes partially regulated by mTOR as well as sensitive to Torin 2 inhibition.