The influence of heme oxygenase-1 in mTOR pathway activation in macrophages

• Grant number: 14/17545-2
• Support Opportunities: Scholarships abroad - Research Internship - Scientific Initiation
• Start date: November 01, 2014
• End date: February 28, 2015
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Mariane Tami Amano
• Grantee: Marcela Teatin Latancia
• Supervisor: Leo Edmond Otterbein
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: Harvard University, Boston, United States
• Associated to the scholarship: 13/09563-8 - Modulation of the mTOR pathway through Toll-like receptors activation in dendritic cells and their effects on sepsis, BP.IC

Abstract

Macrophages are antigen-presenting cells (APCs) and are essential first responders that trigger innate immune responses leading to appropriate adaptive immune responses. They express Toll like receptors on their surface and it is this family of receptors that recognize pathogen associated molecular patterns (PAMPs) and activate the macrophage. Activated macrophages increase expression of stress response genes such as heme oxygenase (HO-1). HO-1 is what is known as a protective gene; its induction provides important survival capabilities for the cell. HO-1 accomplishes this primarily by generating bioactive products including the gas carbon monoxide (CO) and biliverdin (BV). These molecules protect the cell and serve an important role in modulating overwhelming immune responses such as sepsis. The effect of HO-1, CO and BV on macrophages are still unclear. Recent novel findings show that PI3K and mTOR pathways are important. The mTOR pathway is present in macrophages and other cells types and influences metabolism and cell growth as well as the immune response. Our aim is to unravel how HO-1 and its products may modulate mTOR complexes and influence macrophage fate. We will cultivate macrophages and stimulate them with LPS or bacteria and assess if mTOR complexes are activated. Then, using Cre-lox technology, we will harvest bone-marrow macrophages from mice lacking HO-1 or BVR specifically in macrophages (Lyz-cre-Hmox1fl/fl and Lyz-cre-BVRfl/fl). We will test whether mTOR complexes are differently activated in the presence and absence of HO-1. Therefore, we intend to unveil the mechanisms by which mTORC1 and mTORC2 are activated by HO-1 and one or more if its products. (AU)