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Laboratory of Biotechnology applied to Pharmacology  

Lab. A. Maggi

 

Head
Adriana Maggi, Full Professor    adriana.maggi@unimi.it

Team
Valeria Benedusi, post doc valeria.benedusi@unimi.it
Giorgia Calderazzi, PhD student giorgia.calderazzi@unimi.it
Paolo Ciana, Assistant Professor paolo.ciana@unimi.it
Sara Della Torre, post doc sara.dellatorre@unimi.it
Roberta Fontana, PhD student roberta.fontana@unimi.it
Clara Meda, Technician clara.meda@unimi.it
Sara Valeria Occhipinti, Fellow student saravaleria.occhipinti@unimi.it
Monica Rebecchi, Technician monica.rebecchi@unimi.it
Marta tocchetti, post doc marta.tocchetti@unimi.it
Cristina Vantaggiato, Technician cristina.vantaggiato@unimi.it
Elisabetta Vegeto, Associate Professor elisabetta.vegeto@unimi.it
Alessandro Villa, post doc alessandromaria.villa@unimi.it

 

Lines of Research

Estrogen action and the physiopathology of  female aging

Research leader: prof. Adriana Maggi

In the past years the lab has conceived and generated an innovative transgenic mouse model where the generalized expression of the estrogen-driven luciferase reporter enabled the detailed analysis of estrogen receptor activity in living animals thus facilitating the spatio-temporal vision of estrogens in action.  This unique tool revealed to be most suitable for a more rational and predictive preclinical evaluation of estrogen receptor ligands, but also for the study of  estrogen physiological activity. In addition, the innovative nature of the technology developed for the realization of the mouse was patented and represented the core technology for the foundation of a spin-off of the University of Milan: TOP S.r.l.

The analysis of estrogen receptor activity in mice showed that in female mammals  most organs involved in the control of energy metabolism are a relevant target for estrogen thus underlining the major role of these hormones as modulators of reproduction and metabolism: two functions strictly intertwined in female physiology . The work of the lab is now devoted to the full understanding of the mechanisms underlying estrogen control of metabolic functions which occurs in liver, pancreas, central nervous system and adipose tissue with the aim of understanding its relevance in the etiopathology  of the disorders associated with the cessation of ovarian functions which common denominator is an altered control of energy metabolism.

The final aim is the identification of novel pathways relevant for woman aging and potential target for innovative therapies. 

Selection of publications:
1. Villa A, Della Torre S, Stell A, Cook J, Brown M and Maggi A. A tetradian oscillation of Estrogen Receptor alpha is necessary to prevent liver lipid deposition. Proc. Natl. Acad. Sci. (USA) 2012 109:11806-11
2. Della Torre S, Rando G, Meda C, Stell A, Chambon P, Krust A, Ibarra C, Magni P, Ciana P, Maggi A. Amino acid-dependent activation of liver estrogen receptor alpha integrates metabolic and reproductive functions via IGF-1. Cell Metab. 2011, 13:205-14.
3. Della Torre S, Biserni A, Rando G, Monteleone G, Ciana P, Komm B, Maggi A. The conundrum of estrogen receptor oscillatory activity in the search for an appropriate hormone replacement therapy.  Endocrinology 2011, 152:2256-65
4. Rando G, Horner D, Biserni A, Ramachandran B, Caruso D, Ciana P, Komm B, Maggi A. An innovative method to classify SERMs based on the dynamics of estrogen receptor transcriptional activity in living animals. Mol Endocrinol. 2010 24:735-44.
5. Della Torre S, Benedusi V, Fontana R and Maggi A. Energy metabolism and reproduction, an ancestral balance to be preserved for women health. Nature Review in Endocrinology, submitted

Techniques
Biochemical, molecular and cellular biology techniques and bioinformatic and multimodal imaging analyses are utilized in the laboratory together with the use and exploitation of engineered biotechnological systems.

Patents
Transgenic mouse for screening and for studies of the pharmacodynamics and pharmacokinetics of ligands acting on intracellular receptors, and method for the preparation thereof. Italian patent No. ITA MI001503 ; EU patent No. EP 1298988B1 US patent No. 7,943,815.  Inventors: Paolo Ciana and Adriana Maggi

 

Pharmacology of estrogen receptors and regulation of the inflammatory response

Principal Investigator: prof. Elisabetta Vegeto

Based on the evidence showing a key role played by estrogens in preventing inflammation-based pathologies, such as osteoporosis, cardiovascular and neurodegenerative diseases, this laboratory studies the activity of estrogens on genomic and cellular processes regulating the inflammatory response, with the aim to identify molecular targets exploitable to develop innovative therapies, which can help preventing tissue degeneration and improving efficacy and safety of estrogenic therapies.

Techniques
Biochemical, molecular and cellular biology techniques are utilized in the laboratory, together with the use and exploitation of engineered biotechnological systems.

References
1. Benedusi V, Meda C, Della Torre S, Monteleone G, Vegeto E and Maggi A. (2012) A lack of ovarian function increases neuroinflammation in aged mice. Endocrinology 153:2777-88
2. Vegeto E, Cuzzocrea S, Crisafulli C, Mazzon E, Sala A, Krust A, Maggi A (2010) Estrogen receptor-alpha as a drug target candidate for preventing lung inflammation. Endocrinology 151:174-84
3. E. Vegeto, Belcredito S., Ghisletti S., Meda C., Etteri S. and Maggi A. (2006) The endogenous estrogen status regulates microglia reactivity in animal models of neuroinflammation. Endocrinology 147:2263-72
4. S. Ghisletti, C. Meda, A. Maggi and E. Vegeto (2005) 17beta-estradiol inhibits inflammatory gene expression by controlling NF-kB intracellular localization. Molecular and Cellular Biology 25:2957-68
5. Vegeto E., Belcredito S., Brusadelli A., Ghisletti S., Krust A., Dupont S., Ciana P., Chambon P. and Maggi A. (2003) Estogen receptor alpha mediates the anti-inflammatory activity of estroadiol. Proc Natl Acad Sci USA 100:9614-19 
 

Imaging of estrogen receptor activity during the neoplastic transformation of the mammary gland.

Principal investigator: dr Paolo Ciana

In the latest fifteen years, the laboratory generated cell and animal models for the multidimensional measurements of molecular events occurring during neoplastic transformation by using molecular imaging technologies (1-5). These models are currently applied to the study of mammary carcinogenesis with the purpose to identify novel biomarkers of tumor progression and novel drug targets (6-8) for this neoplastic disease, which represents today the first  cause of cancer death in women.

Research project. The estrogen receptor (ER) is a key player in the development of hormone-dependent breast cancers and therapies against this receptor are among the most efficacious treatment available for patients. The laboratory investigates the dynamic of ER activation at systemic level (from the initial tumor stages until  the acquisition of a full transformed phenotype) in mouse models of breast cancer by using a non-invasive molecular imaging approach (1-5). Our data suggest that the process of mammary transformation occur through sequential cycles of ER activations involving the immune system, and that this dynamic is shared by different neoplastic transformation pathways, since it  was observed in all the models of breast cancer tested so far. The research has been initially carried out at systemic level, now it is investigated at a molecular level through different approaches:

i. genomic analysis aimed at the identification of specific signals underlying the early steps of breast tumorigenesis: translation of these results is pursuit by the lab in strict collaboration with clinical oncologists (6);

ii. molecular characterization of nodal points, at the cross-road between cancer and inflammation signals, that can be used as therapeutic targets for chemoprevention (7);

iii. molecular characterization of the mechanism underlying ER activation during the neoplastic transformation of the mammary gland and the progression towards the development of hormone-refractory cancers in humans (8).

Techniques
The lab is applying a multidisciplinary approach based on molecular imaging, reporter technology and mouse transgenesis to study the dynamic of molecular events involved in tumorigenesis. These studies are complemented by the use of  classical  biochemical, molecular/cellular biology and histology techniques as well as by genomic analysis.

References
1- Ciana P., Raviscioni M., Vegeto E., Mussi P., Que I., Parker M., Lowik C. and Maggi A. In vivo imaging of transcriptionally active estrogen receptor. Nature Medicine (2003) 9: 82.
2- Stell A, Biserni A, Della Torre S, Rando G, Ramachandran B, Ottobrini L, Lucignani G, Maggi A, Ciana P. Cancer modeling: modern imaging applications in the generation of novel animal model systems to study cancer progression and therapy. Int J Biochem Cell Biol. 2007;39(7-8):1288-96.
3- Dondi D, Piccolella M, Biserni A, Della Torre S, Ramachandran B, Locatelli A, Rusmini P, Sau D, Caruso D, Maggi A, Ciana P*, Poletti A*. Estrogen receptor beta and the progression of prostate cancer: role of 5alpha-androstane-3beta,17beta-diol. Endocr Relat Cancer. 2010 Jul 28;17(3):731-42. *equally contributed
4- Ramachandran B., Stell A., Maravigna L., Maggi A., Ciana P. Novel insights on imaging sex-hormone-dependent tumourigenesis in vivo. Endocr Relat Cancer. (2011) Apr 2;18(3):R41-51.
5- Goeman F., Manni I., Artuso S., Ramachandran B., Toietta G., Bossi G., Rando G., Cencioni C., Germoni S., Straino S., Capogrossi M., Bacchetti S., Maggi A., Sacchi A., Ciana P* and Piaggio G* Molecular imaging of the nuclear factor-Y trascriptional activity maps proliferarion sites in live animals. Molecular Biology of the Cell, (2012) 23: 1467-1474 *corresponding authors

Patents
1-Maggi A.C.,Ciana P.,Piaggio G.,Frauke G.,Sacchi A.,Tiveron C. (2009). Transgenic animal for screening of compounds that modulate cell proliferation, and its use in the pharmaceutical field. MI2009A002023, estensione europea EP10014685 e americana US12/926,435;
2- Santaniello E, Meroni G, Ciana P, Maggi A. (2009). “Metodo di sintesi di luciferina e deidroluciferina”. MI2009A000294;
3- Ciana P., Trincavelli M.l., Verderio C., Rovati G.E., Abbracchio M.P., Martini C. (2006). Gpr17 modulators, method of screening and uses thereof. PCT/EP2005/011157;
4- Maggi A.,, Ciana P. (2000). Topo transgenico per lo screening e per studi di farmacodinamica e farmacocinetica di ligandi attivi sul recettore degli estrogeni e sui recettori intracellulari, e metodo per la sua preparazione. No. ITA MI001503, estensione Europea EP 1298988B1 e americana US patent No. 7,943,815.

 

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