Molecular mechanisms underlying TNF-induced and repression gene expression in cachexia

• Grant number: 16/08294-1
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Start date: July 07, 2016
• End date: July 06, 2017
• Field of knowledge: Biological Sciences - Morphology - Histology
• Principal Investigator: Robson Francisco Carvalho
• Grantee: Geysson Javier Fernandez Garcia
• Supervisor: Alexander Hoffmann
• Host Institution: Instituto de Biociências (IBB). Universidade Estadual Paulista (UNESP). Campus de Botucatu. Botucatu , SP, Brazil
• Institution abroad: University of California, Los Angeles (UCLA), United States
• Associated to the scholarship: 14/13941-0 - Multilayer-omics analysis of cancer cachexia: integrative approach to identify biomarkers and drug targets, BP.DR

Abstract

Pro-inflammatory cytokines such as Tumor Necrosis Factor alpha (TNF) has been implicated in the pathogenesis of skeletal muscle atrophy in cachexia, a metabolic syndrome commonly associated with many chronic systemic inflammatory diseases such as cancer and AIDS. Although the up-regulation of mRNA levels in response to TNF signaling has been studied extensively in the context of immune activation, such as in macrophages, the mechanisms that control the gene repression program, which is of particular relevance in muscle cells, are still poorly understood. Whereas transcriptional activators, most prominently NFkB are known to control gene activation, the mechanisms for gene repression may not only involve DNA binding proteins that regulate mRNA initiation, but also mechanisms that control mRNA decay. Here we propose to study at a genome-wide level, the effect of TNF signaling on RNA metabolic events that regulate gene induction and repression programs in muscle cells. Fine-grained datasets will distinguish between mRNA synthesis and mRNA degradation, and a mathematical modeling approach will be used to derive kinetic parameters and identify key mechanisms of control for each of the hundreds of affected genes. This knowledge will help to shed light on how the interplay between TNF signaling and RNA metabolism leads to gene expression program related to muscle atrophy in cancer cachexia. The project also has a methodological goal, which consists of setting up a full experimental and analytical workflow to profile dynamic gene expression and dynamic data on RNA metabolism in muscle wasting. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

FERNANDEZ, GEYSSON JAVIER; FERREIRA, JUAREZ HENRIQUE; VECHETTI JR, IVAN JOSE; DE MORAES, LEONARDO NAZARIO; CURY, SARAH SANTILONI; FREIRE, PAULA PACCIELLI; GUTIERREZ, JAYSON; FERRETTI, RENATO; DAL-PAI-SILVA, MAELI; ROGATTO, SILVIA REGINA; et al. MicroRNA-mRNA Co-sequencing Identifies Transcriptional and Post-transcriptional Regulatory Networks Underlying Muscle Wasting in Cancer Cachexia. FRONTIERS IN GENETICS, v. 11, MAY 29 2020. (13/02005-0, 12/13961-6, 13/50343-1, 16/08294-1, 14/13941-0, 11/16282-0)