Head:	Elisabetta Vegeto (Associate Professor, Pharmacology)
Team members:	Sara Della Torre (Assistant professor; Biochemistry) Giovanna Pepe (Postdoctoral fellow; Pharmacology) Chiara Sfogliarini (Scholarship holder) Arianna Dolce (Scholarship holder)
Advisor:	Adriana Maggi (Professor Emeritus; Pharmacology)

 
 
GENERAL DESCRIPTION

In mammals, there is a delicate balance between metabolism and the ability to survive harmful stimuli; alterations of this balance have significant implications in a number of diseases such as obesity, diabetes and diseases of the cardiovascular system. Studies of this laboratory highlighted the importance of sex hormones, in particular estrogens, in balancing the immune system and energetic metabolism, demonstrating that estrogens exert key action on the innate immune response, favoring the resolution of inflammation and inducing a tolerant phenotype in immune cells, and at the same time regulating the ability of metabolic organs to use, produce and store energy. Using up to date molecular technologies, these studies help to explain the different incidence of metabolic and inflammatory diseases in the two sexes and offer a new opportunity to translate this knowledge into more effective therapeutic interventions that help relieving disease costs for the modern society. Research projects are aimed at understanding the molecular and cellular basis of gender differences in innate immunity and energy metabolism, with the aim of identifying innovative drug targets for the treatment of metabolic diseases and inflammatory dysfunctions, particularly in the central nervous system and reproductive axis. Furthermore, our research is also aimed at devising and developing innovative biotechnological models for pharmacological applications.

RESEARCH TOPICS
1. Molecular biology and pharmacology of gender differences in metabolism
2. Characterization of sexual differences in innate immune cells
3. Study of the immunomodulatory mechanisms of drugs acting on the estrogen receptor
4. Pharmacological biotechnologies for the control of gene expression

DESCRIPTION OF RESEARCH TOPICS

1. Molecular biology and pharmacology of gender differences in metabolism
Using innovative molecular imaging modalities, the laboratory has shown for the first time that the liver is one of the most important targets of estrogens. In fact, the estrogen receptor-alpha acts as a sensor of ovarian activity and nutritional state in this organ and regulates reproductive functions in close relationship with energy metabolism. This phenomenon has significant consequences on hepatic metabolism itself, strongly contributing to hepatic sexual dimorphism and to sex differences in susceptibility to liver diseases as well as other metabolic diseases. Our current studies are aimed at understanding the physio-pathological response of individuals of both sexes to dietary or hormonal stimulations for the understanding of the involvement of hepatic estrogen receptor-alpha in the sex-specific susceptibility to metabolic diseases.

Main collaborations:
• N. Henriette Uhlenhaut e Fabiana Quagliarini. Helmholtz Diabetes Center (HDC) e German Center for Diabetes Research (DZD), Helmholtz Zentrum, Muenchen, Germany.
• Ken A. Dyar. Helmholtz Diabetes Center (HDC) e German Center for Diabetes Research (DZD), Helmholtz Zentrum, Muenchen, Germany.
• Luca Valenti. Ospedale Maggiore e Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Università degli Studi di Milano.
• Monica Gomaraschi. Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano.
• Emanuela Tolosano, Dipartimento di Farmacologia, Università degli Studi di Torino.
• Nico Mitro. Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano.
• Carola Eva, Dipartimento di Farmacologia, Università degli Studi di Torino.

2. Molecular characterization of sexual differences in innate immune cells
Research from the laboratory has recently discovered the fundamental role of sex in the involvement of innate immunity cells, in particular microglia, in brain physiopathology. The rapid progress of these studies is linked to the development of animal and cell models created by our laboratory and of investigation methodologies based on bioluminescence and NMR. Since men and women have different susceptibility to neurodegenerative as well as other inflammation-based diseases, this research is aimed at understanding the molecular basis of sexual differences in the reactivity and adaptation of macrophages to pathological damages, in order to identify new drug targets useful for both sexes.

Main collaborations:
• Andreas Jacobs European Institute for Molecular Imaging (Eimi), University of Münster, Münster, Germany
• Albert D. Windhorst. Department of Radiology & Nuclear Medicine, Amsterdam Neuroscience, VU University Medical Center, Amsterdam, the Netherlands
• Anna Planas, Institute of Biomedical Research of Barcelona, Spanish Council for Scientific Research, University of Barcelona, Spain

3. Study of the immunomodulatory mechanisms of drugs acting on estrogen receptors
In addition to its activity in reproductive tissues, estrogens regulate other important processes that include innate immunity and the inflammatory response. Our studies showed that endogenous estrogens are able to influence the number and function of macrophages, key innate immune cells, in a number of different organs, such as the brain, lungs and peritoneum, and to induce an immune response associated with tissue remodeling. The goal of this line of research is to study the molecular mechanism underlying the action of the estrogen receptor in the inflammatory response and in the communication between macrophages and the microenvironment, in both physiological and pathological contexts. Using innovative experimental models, including reporter animals of the anti-fibrotic and antioxidant response, cell transplantation and 2D and 3D culture systems, the aim of this activity is to exploit acquired knowledge to develop novel immunoregulatory drugs. Our studies are focused on clinical applications that necessitate a pharmacological control of the inflammatory response and include infections, neurodegenerative diseases, endometriosis, pancreatitis and cancer.

Main collaborations:
• Massimo Locati, Department of Medical Biotechnologies and Translational Medicine, University of Milan
• Eugenio Scanziani and Camilla Recordati, Department of Veterinary Medicine, University of Milan
• Paola Viganò, Laboratory of technologies for assisted reproduction, IRCCS Policlinico, Milan
• Margherita Turco, Center for trophoblast research, University of Cambridge, UK
• Rossella Nappi, Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, University of Pavia
• Massimo Candiani, IRCCS San Raffaele Hospital, Milan
• Loris Rizzello, Department of Pharmaceutical Sciences, University of Milan
• Tommaso Simoncini, Department of Clinical and Experimental Medicine, University of Pisa
• Chiara Bolego, Department of Pharmaceutical Sciences, University of Padua

4. Pharmacological biotechnologies for the control of gene expression
One of the main interests of the research group is the study of the mechanism of action of transcription factors regulated by endocrine, proliferative, inflammatory and oxidative stress signals. This research is aimed at the generation of animal and cellular models which allow to visualize the activity of these factors by non-invasive imaging, along with omics’ methodologies. Thanks to their originality and experimental validity, these models are widely used in preclinical research, since they allow to study the molecular mechanisms of regulation of physio-pathological processes. Current research is aimed at the generation of reporter models amenable for the imaging of macrophage polarization in living organisms, for studying the inflammatory process associated with human pathologies and aging.

Main collaborations:
• Albert D. Windhorst. Department of Radiology & Nuclear Medicine, Amsterdam Neuroscience, VU University Medical Center, Amsterdam, the Netherlands
• Matthew J. Hardman MJ. The Healing Foundation Center, Faculty of Life Sciences, University of Manchester, Manchester, UK
• C. Ohlsson. Center for Bone and Arthritis Research and Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden
• Andreas Jacobs European Institute for Molecular Imaging (Eimi), University of Münster, Münster, Germany