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Laboratory of Pharmacology of Dyslipidemias and Atherosclerosis  

Lab. Franceschini

 

Director
Guido Franceschini, Full Professor    guido.franceschini@unimi.it   

Team
Laura Calabresi, Associate Professor laura.calabresi@unimi.it
Giulia Chiesa, Assistant Professor giulia.chiesa@unimi.it
Cinzia Parolini, Technician cinzia.parolini@unimi.it
Marco Busnelli, Fellow
Federica Dellera, Fellow
Giulia Ganzetti, Fellow
Monica Gomaraschi, Post-Doctoral Fellow
Stefano Manzini, Fellow
Alice Ossoli, PhD Student
Sara Simonelli, Post-Doctoral Fellow
Cinzia Vitali, Fellow

 

Research Activity

Research activity is focused on an improved understanding of the physiology and pathology of human lipoproteins and of the efficacy and mode of action of agents affecting lipid/lipoprotein metabolism and atherosclerosis.

  • Pathophysiology of high density lipoproteins (HDL)

HDL pathophysiology is investigated through an integrated genetic, biochemical and clinical approach involving (i) identification of families with rare disorders of HDL metabolism, (ii) definition of the genetic defect, and (iii) characterization of the biochemical and clinical phenotype. These studies are complemented with in vitro investigations of the effects of purified HDL fractions on reverse cholesterol transport and inflammation.

  • HDL as therapeutic agent

The potential of “HDL-therapy”, a novel approach to the prevention and treatment of cardiovascular diseases based on the administration of synthetic HDL (sHDL), is investigated through: (i) the structural characterization of sHDL of different composition, (ii) the definition of sHDL activity in cultured cells and isolated organs, (iii) the description of in vivo effects of sHDL in suitable animal models.

  • Efficacy and mode of action of lipid-lowering and anti-atherosclerotic therapies in humans

Available and novel therapies affecting lipid/lipoprotein metabolism and atherosclerosis are investigated in patients with various forms of dyslipidemia, through the evaluation of their effects on lipid/lipoprotein levels, lipoprotein structure and function, enzymes involved in lipoprotein metabolism.

  • Animal models for the investigation of lipoprotein pathophysiology

Lipoprotein pathophysiology is investigated through (i) generation of mice that express human proteins involved in lipoprotein metabolism, (ii) definition of genotype-phenotype relationships, (iii) characterization of specific pathways of lipid/lipoprotein metabolism.

  • Animal models for the development of anti-atherosclerotic therapies

The effects of novel dietary or pharmacologic treatments on atherosclerosis development and regression is investigated in vivo by invasive and non-invasive techniques, and ex-vivo by histology.

 

Techniques

Lipoprotein fractionation and characterization: ultracentrifugation, chromatography , electrophoresis (SDS-PAGE, IEF, non-denaturing electrophoresis), immunoassays.

Cell culture: endothelial cells, primary monocytes, kidney cells (tubular, mesangial, podocytes).

Molecular biology: gene sequencing, PCR, RT-PCR, RNA extraction from cells/tissues, Western blotting.

Animal models: atherosclerosis induction in rabbits by electrical injury; restenosis induction in rats by balloon injury; histology and immunohistochemistry; generation and characterization of transgenic mice.

In vivo diagnostic techniques: intravascular ultrasound and magnetic resonance imaging of atherosclerotic plaques in rabbits; image analysis.

 

Selected Publications

Calabresi L, Baldassarre D, Castelnuovo S, Conca P, Bocchi L, Candini C, Frigerio B, Amato M, Sirtori CR, Alessandrini P, Arca M, Boscutti G, Cattin L, Gesualdo L, Sampietro T, Vaudo G, Veglia F, Calandra S, Franceschini G (2009) Functional lecithin: cholesterol acyltransferase is not required for efficient

atheroprotection in humans. Circulation120:628-35.

Calabresi L, Gomaraschi M, Rossoni G, Franceschini G (2006) Synthetic high density lipoproteins for the treatment of myocardial ischemia/reperfusion injury. Pharmacol Ther111:836-54.

Calabresi L, Pisciotta L, Costantin A, Frigerio I, Eberini I, Alessandrini P,Arca M, Bittolo Bon G, Boscutti G, Busnach G, Frascà G, Gesualdo L, Gigante M, Lupattelli G, Montali A, Pizzolitto S, Rabbone I, Rolleri M, Ruotolo G, Sampietro T, Sessa A, Vaudo G, Cantafora A, Veglia F, Calandra S, Bertolini S, Franceschini G (2005) The molecular basis of lecithin:cholesterol acyltransferase deficiency syndromes: a comprehensive study of molecular and biochemical findings in 13 unrelated Italian families. ArteriosclerThromb Vasc Biol 25:1972-8.

Calabresi L, Vecchio G, Longhi R, Gianazza E, Palm G, Wadensten H, Hammarström A, Olsson A, Karlström A, Sejlitz T, Ageland H, Sirtori CR, Franceschini G (1994) Molecular characterization of native and recombinant apolipoprotein A-IMilano dimer. The introduction of an interchain disulfide bridge remarkably alters the physicochemical properties of apolipoprotein A-I. J Biol Chem269:32168-74.

Chiesa G, Monteggia E, Marchesi M, Lorenzon P, Laucello M, Lorusso V, Di Mario C, Karvouni E, Newton RS, Bisgaier CL, Franceschini G, Sirtori CR (2002) Recombinant apolipoprotein A-IMilano infusion into rabbit carotid artery rapidly removes lipid from fatty streaks. Circ Res90:974-80.

Chiesa G, Stolzfus LJ, Michelagnoli S, Bielicki JK, Santi M, Forte TM, Sirtori CR, Franceschini G, Rubin EM (1998) Elevated triglycerides and low HDL cholesterol in transgenic mice expressing human apolipoprotein A-IMilano. Atherosclerosis136:139-46

Franceschini G, Sirtori CR, Capurso A, Weisgraber K, Bersot T, Mahley RW (1980) AIMilano apoprotein. Decreased high density lipoprotein cholesterol levels with significant lipoprotein modifications in an Italian family. J Clin Invest 66:892-900.

Franceschini G, Sirtori M, Vaccarino V, Gianfranceschi G, Rezzonico L, Chie­sa G, Sirtori CR (1989) Mechanisms of HDL reduction after probucol: changes in HDL subfractions and increased reverse cholesteryl ester transfer. Arteriosclerosis 9:462-9.

Gomaraschi M, Baldassarre D, Amato M, Eligini S, Conca P, Sirtori CR, Franceschini G, Calabresi L (2007) Normal vascular function despite low levels of high-density lipoprotein cholesterol in carriers of the apolipoprotein A-IMilano mutant. Circulation116:2165-72

Simonelli S, Gianazza E, Mombelli G, Bondioli A, Ferraro G, Penco S, Sirtori CR, Franceschini G, Calabresi L (2012) Severe HDL deficiency associated with autoantibodies against lecithin:cholesterol acyltransferase in non-Hodgkin lymphoma. Arch Intern Med172:179-81.

 

Patents

Sirtori CR, Sidoli A, Franceschini G, Baralle T; Expression of human apolipoprotein A-IMilano in yeast; patents EP 469017B1, AU 641389, IT 1229996.

Sirtori CR, Franceschini G, Abrahmsen L, Holmgren E, Lake M, Nilsson B, Chmielewska J, Lind P; Dimer of molecular variant of apolipoprotein and processes for the production thereof; patents US 5,876,968, US 6,617,134.

Bisgaier C, Pape M, Johansson J, Franceschini G; Methods and compositions for the treatment of ischemic reperfusion; patents US 60/381,653, US 60/405,478.

 

Links

www.lcat.it

 

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