The role of PPARgamma-dependent communication pathways between brain endothelial cells and perivascular macrophages in immune-to-brain communication

• Applicant: Jan-Sebastian Grigoleit, Ph.D.
• Subject Area: Cognitive, Systems and Behavioural Neurobiology
• Term: from 2013 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 240136214

Episodes of systemic infection or inflammation engage the innate immune system to release pro-inflammatory cytokines that can act on the brain to initiate an array of acute phase responses, including activation of the hypothalamo-pituitary-adrenal (HPA) axis. Glucocorticoid mediators of HPA function serve critical metabolic and immunoregulatory roles that facilitate coping with the immediate threat. Previous work on this project by Dr. Paul Sawchenko and his colleagues has defined a model for a neurovascular circuit responsible for immune-mediated HPA engagement that involves binding of circulating cytokines (e.g., interleukin-1; IL-1) by cerebrovascular endothelial cells (ECs), which activate a resident macrophage cell type in the perivascular space (perivascular cells; PVCs) to manifest or enhance cyclooxygenase (COX) expression and prostaglandin E2 (PGE2) release. ECs may also contribute to inducible prostanoid synthesis, and their ability to do so is negatively regulated by PVCs. PGE2 of PVC and/or EC origin then acts in a paracrine fashion to stimulate catecholamine neurons in the medulla that express PGE2 receptors, and, by way of their well-documented axonal projections, parvocellular neurosecretory neurons that express corticotropin-releasing factor (CRF) to initiate HPA output. Here in accordance with Dr. Sawchenko I propose experiments to further develop this model, test its validity/generality and to explore the therapeutic potential of insights gleaned from Dr. Sawchenko's work for intervening in CNS inflammatory disease. One focus of the proposed experiments will be the involvement of peroxisome proliferator-activated receptor gamma (PPARg)-dependent signaling mechanisms.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Paul E. Sawchenko, Ph.D.