The role of the a7nAChR receptor in preventing the activation of the ceramide pathway and endoplasmic reticulum stress

• Grant number: 24/05831-2
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
• Start date: September 01, 2024
• End date: August 29, 2025
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Marcio Alberto Torsoni
• Grantee: Ísis de Cássia Alves Martins
• Supervisor: Herve Le Stunff
• Host Institution: Faculdade de Ciências Aplicadas (FCA). Universidade Estadual de Campinas (UNICAMP). Limeira , SP, Brazil
• Institution abroad: Institut Des Neurosciences Paris-Saclay, France
• Associated to the scholarship: 20/06757-0 - Modulation of a7nAChR receptor expression by inflammatory processes and the effect on the activity of hypothalamic neurons that participate in energy homeostasis, BP.DD

Abstract

Studies showed that short-term consumption of a diet rich in saturated fatty acids activates inflammatory pathways in the hypothalamus, supporting the idea that inflammatory processes have a fundamental role in the development of metabolic disorders that are associated with hypothalamic activity. The lipids species that accumulate under these conditions, sphingolipids such as ceramide or its metabolites are amongst the most deleterious because they disrupt insulin sensitivity. Nicotinic acetylcholine receptors (nAChRs) have wide expression in the central nervous system and recent studies showed the ability of these receptors to activate signal transduction pathways that result in inhibition of the transcription of pro-inflammatory cytokines. This mechanism is called cholinergic anti-inflammatory reflex. The cholinergic anti-inflammatory reflex has been studied as a therapeutic target for diseases associated with nutritional disorders such as obesity and diabetes. Recently we showed that consumption of a high-fat diet (HFD) for three days was able to reduce the hypothalamic expression of the a7nAChR receptor and still makes the hypothalamus more susceptible to inflammatory damage. On the other hand, the selective receptor agonist reduced the potency of the inflammatory response. These results showed that inflammatory process induced by LPS or HFD is capable of reduce the a7nAChR expression, in an early way, and make the cell or cell ambient more permissive to other inflammatory process. Our unpublished data show that the treatment of a hypothalamic neuronal cell line with LPS or saturated fatty acid such as palmitate caused an increase in pro-inflammatory cytokines and genes related to other mechanisms like endoplasmic reticulum stress and apoptosis, and that the use of the selective a7nAChR receptor agonist reduced these effects. In this context, we intend to investigate and understand the role of the a7nAChR receptor in preventing the activation of the ceramide pathway and endoplasmic reticulum stress and the molecular mechanisms induced by inflammatory stimuli in the presence or absence of this receptor. For this purpose, we intended expand our knowledge in the research of a7nAChR and bring new methodological approaches to contribute to the development and improvement of techniques that will add to our scientific and academic environment. Innovative techniques will be imported and improved, especially regarding the assessment of lipid metabolism by lipidomic analysis and lipid signaling and its effects in the a7nAChR on central nervous system.