Objective The era of molecular genetics has enabled the mechanistic dissection of brain circuits as well as the immune system in spectacular ways. However, the molecular and cellular organization of the sympathetic nervous system (SNS), which innervates all known organs, is essentially unexplored. In an attempt to push this frontier, we have recently uncovered a direct physical functional connection between the SNS and the adipose tissue. Further, we found this neuro-adipose junction to drive lipolysis and fat mass reduction (1). In this proposal we aim to define the molecular mechanisms that link SNS neurons, the immune system and the adipose tissue. A major entry point is our recent discovery of a novel population of Sympathetic Associated Macrophages (SAMs) that suppress the output of SNS. We propose to unravel their contribution to obesity in rodents (Aim 1) and in humans (Aim 2). Another major objective of this proposal is to establish a functional and molecular neuronanatomical map of the SNS, which defines subpopulations of neurons that specifically innervate fat (Aim 3). To achieve this, we will build molecular genetics tools for rapid non-invasive optocoustic visualization and functional probing of SNS circuits. A molecular and realistic atlas of the SNS will allow us to systematically access the functional anatomy of one of the most elusive tissues of the mammalian body and will form a blueprint upon which our neuroimmune mechanistic studies can be build. Our identification of the fundamental biological mechanisms that govern the neuro-adipose junction will set the stage for a new anti-obesity therapy that would circumvent the challenge of drug delivery to the brain, i.e. by targeting an excitatory drug directly to SAMs or sympathetic inputs in adipose tissue. Fields of science natural sciencesbiological sciencesgeneticsnatural sciencesbiological sciencesmolecular biologymolecular geneticsmedical and health sciencesbasic medicineanatomy and morphologymedical and health sciencesbasic medicineimmunologymedical and health scienceshealth sciencesnutritionobesity Keywords Obesity Optoacoustics macrophages chemogenetics optogenetics mouse models neurocircuits Programme(s) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Topic(s) ERC-2017-COG - ERC Consolidator Grant Call for proposal ERC-2017-COG See other projects for this call Funding Scheme ERC-COG - Consolidator Grant Host institution THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD Net EU contribution € 2 029 175,00 Address WELLINGTON SQUARE UNIVERSITY OFFICES OX1 2JD Oxford United Kingdom See on map Region South East (England) Berkshire, Buckinghamshire and Oxfordshire Oxfordshire Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 2 029 175,00 Beneficiaries (1) Sort alphabetically Sort by Net EU contribution Expand all Collapse all THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD United Kingdom Net EU contribution € 2 029 175,00 Address WELLINGTON SQUARE UNIVERSITY OFFICES OX1 2JD Oxford See on map Region South East (England) Berkshire, Buckinghamshire and Oxfordshire Oxfordshire Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 2 029 175,00
