Mechanisms of inflammation-induced sensitization of peripheral sensory systems

• Grant number: 21/13560-0
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: April 01, 2022
• End date: March 31, 2023
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Eduardo Colombari
• Grantee: Pedro Lourenço Katayama
• Supervisor: Clifford John Woolf
• Host Institution: Faculdade de Odontologia (FOAr). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
• Institution abroad: Harvard University, Boston, United States
• Associated to the scholarship: 19/11196-0 - Mechanisms and neural circuits involved in the interaction between peripheral inflammation and sympathoexcitation in Renovascular Hypertension, BP.PD

Abstract

The nervous and immune systems interact in a bidirectional manner, but the precise mechanisms governing this interplay are still unclear. Recently, we identified a previously unrecognized mechanism of neuroimmune interaction in which peripheral sensory organs (i.e., the carotid bodies) can detect the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) in the blood, activating central sympathetic networks to modulate acute systemic inflammation. Besides, there is an established body of evidence indicating that TNF-alpha and other inflammatory ligands can impact the activity of distinct cell populations contained in diverse peripheral sensory ganglia (i.e., dorsal root ganglion, nodose ganglion). Furthermore, in experimental models of sensory hypersensitivity (e.g., allergen-induced bronchial hyperresponsiveness, inflammatory pain hypersensitivity), it has been shown that chronic inflammation sensitizes cells within peripheral sensory organs/ganglia. However, the role of specific inflammation-derived ligands on the activity/sensitization of peripheral sensory systems as well as the exact mechanisms of these phenomena remain uncertain. The purpose of this project is severalfold: 1) To screen for potential inflammatory ligands that activate/sensitize specific peripheral sensory cells. For this, we intend to characterize the transcriptional profile of distinct cell populations contained in dorsal root ganglia (DRG) as well as the transcriptional reprogramming of these cells in inflammation-induced sensory hypersensitivity models; 2) To test the effects of TNF-alpha and other inflammatory ligands on the activation and sensitization of dorsal root ganglion cells and; 3) To investigate the molecular/cellular mechanisms of inflammation-induced sensitization of peripheral sensory cells. To accomplish these goals, we will employ advanced experimental technologies including single-cell RNA-seq, calcium imaging with GCaMP sensors and calcium sensitive dyes, and monitoring of cAMP and PKA activities in vitro and in vivo using novel ultrasensitive biosensors. This multi-faceted approach will provide a multi-level (genetic, molecular, cellular, organismal) perspective to better understand how the immune and the nervous systems interact. (AU)