Abstract
Inflammation is a primordial, complex and highly evolutionary-conserved active response mounted by the innate immune system in response to injury, xenobiotics exposure and infections in order to promote recovery. In addition, inflamamtion is relevant to some special conditions of the body, such as to the succesfull of gestation, and on obesity. Control of the inflammatory response is of Paramount importance in several physiological conditions to avoid pathologies. Indeed, the final goal of inflammation is not only to clear the microenvironment from harmful agents but also to restore tissue homeostasis and to stimulate healing processes where necessary. In its absence, injuries and infections wouldn't be rapidly countered, with unrelenting deterioration of the affected tissue and consequent risks for the entire organism. Therefore, inflammation is the basis of a diversity of diseases. Although widely studied, there is still need to decipher inflammation early stages with its mechanism and its resolution, particularly with the innovative therapeutic angle to identify drug which alt the inflammatory progress while helping resolution and healing.We among other (our collaborator Drs Egle Solito and Mauro Perretti- William Harvey Research Institute, School Medical and Dentistry, Queen Mary University of London (WHRI-SMD-QMUL, UK) have shown a clear role for Annexin A1 (ANXA1; an endogenous mediator of glucocorticoid action) in many biological systems (named granulopoiesis and reproduction) further supporting the idea of AnxA1 as therapeutic tool.Moreover in the lab we have also investigated the modulation of inflammation by peroxisome proliferator activated receptors (PPARs), as well as by the benzodiazepine peripheral receptor (TSPO). Activation of either target affords major modulation on the biology of the neutrophil, intriguingly, their expression, and/or function is controlled by endogenous glucocorticoids and by application of ANXA1. Based on our preliminary data this project aims to:1) Investigate the mechanisms of action of AnxA1 in controlling PMN, macrophage and microglia anti-inflammatory phenotype, focusing on granulopoesis; and the interplay with PPARs and TSPO functions in the peripheral and central nervous system ; 2) Investigate the molecular mechanisms of AnxA1 control on inflammation in reproduction;3) Investigate the role of TSPO in controlling cell differentiation and proliferation particularly in adipocytes responsible for regulating whole-body physiology. Collectivelly, the above aims will identify new targets and will guide on the viable approach for the generation of new molecules exploitable for innovative anti-inflammatory drugs, as well as drug formulations. Therefore, this proposal goes under the umbrella of a thematic project, it requires different expertise, with the involvement of multidisciplinary groups both national and international, to achieve its deliverables and, essentially, its success.This project will be based at the Department of Clinical and Toxicological Analysis, Faculty of Pharmaceutical Sciences, USP (FCF-USP), which, among their research proposals, includes the investigation of the pathophysiology of inflammatory/imune, hematological and metabolic diseases, as well as neoplasia, in order to provide the basis for diagnostics and therapeutics strategies. This is the theme of the graduate program of the department - Pharmacy- Clinical Analyses - rated as 7 grades by CAPES in the Pharmacy area. Therefore, this Project is in accordance to goals of education and research of the Department of Clinical and Toxicological Analysis (FCF). (AU)
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