Modulation of the mTOR pathway through Toll-like receptors activation in dendritic cells and their effects on sepsis

• Grant number: 13/09563-8
• Support type: Scholarships in Brazil - Scientific Initiation
• Effective date (Start): July 01, 2013
• Effective date (End): December 31, 2015
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal researcher: Mariane Tami Amano
• Grantee: Marcela Teatin Latancia
• Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated scholarship(s): 14/17545-2 - The influence of heme oxygenase-1 in mTOR pathway activation in macrophages, BE.EP.IC

Abstract

Sepsis is a Systemic Inflammatory Response Syndrome (SIRS) caused by bacteria's infection, one of the leading causes of death in ICUs. Toll-like receptors (TLR) are able to recognize Pathogen-Associated Molecular Patterns (PAMPs) initiating inflammatory responses and sepsis by activating dendritic cells (DCs). The mTOR pathway, responsible for triggering some metabolic and immunologic responses, is present in DCs and has two complexes, mTORC1 and mTORC2. Our goal is to study how the activation of differents TLRs can modulate the complex mTORC1 / 2 and influence the fate of DCs. Also, check the consequences of this modulation in sepsis. We will cultivate DCs derived from bone marrow of mice and we will stimulate them with different TLR agonists. We will analyze the activation of mTORC1 / 2 by Western Blot, the phenotype of DCs by FACS and the expression of different cytokines by CBA. Then, we will induce sepsis by cecal ligation puncture (CLP) in mice and analyze kidney function as a result of the injury. To confirm the influence of TLRs in mTOR complexes, we will inhibit such complexes with rapamycin, for example. Thus, our project aims to unravel how different TLRs activate the mTOR pathway and their complexes in DCs. Furthermore, as sepsis is closely linked to activation of the immune response by TLRs, possibly using the modulation of mTOR in DCs we might decrease the response caused by sepsis, suggesting new targets for therapy of this syndrome. (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)

AMANO, MARIANE T.; CASTOLDI, ANGELA; ANDRADE-OLIVEIRA, VINICIUS; LATANCIA, MARCELA T.; TERRA, FERNANDA F.; CORREA-COSTA, MATHEUS; BREDA, CRISTIANE N. S.; FELIZARDO, RAPHAEL J. F.; PEREIRA, WELBERT O.; DA SILVA, MARINA B.; MIYAGI, MARIANA Y. S.; AGUIAR, CRISTHIANE F.; HIYANE, I, MEIRE; SILVA, JOAO S.; MOURA, IVAN C.; CAMARA, NIELS O. S. The lack of PI3K gamma favors M1 macrophage polarization and does not prevent kidney diseases progression. International Immunopharmacology, v. 64, p. 151-161, NOV 2018. Web of Science Citations: 4.