Vai al contenuto principale
Logo Università
Logo di Dottorato in Medicina Molecolare

Scuola di Dottorato

Dottorato in Medicina Molecolare

Logo di Dottorato in Medicina Molecolare

Dott.ssa Simona Gallo

  • Dottorato: 27° ciclo
  • Matricola: 304591

Tesi di dottorato

NEW THERAPEUTICAL OBJECTIVES FOR CARDIAC DAMAGE TREATMENT: HGF and HGF-MIMETICS FOR CARDIOPROTECTION

The Hepatocyte Growth Factor (HGF) and its tyrosine kinase receptor Met have a central role in the maintenance of heart functions during both physiological and pathological conditions. HGF/Met axis is well known to induce prosurvival signaling pathways and its activation has been proposed as potential therapeutic approach for various cardiac diseases. Since patient administration of biologically active HGF may be difficult, we propose to use Met activating antibodies as mimetics of HGF.
The project has the objective to investigate the cardioprotective role of Met activating antibodies against two different conditions of cardiac injuries: hypoxia and cardiotoxicity derived from anti-tumoral therapies. We have demonstrated that targeted Met activation is successful in both cardiotoxic conditions to prevent cardiac damage through Met-mediated prosurvival functions, among which anti-apoptotic, anti-autophagic and anti-oxidant activities. Altogether these results suggest that Met activating antibodies represent a new potential tool, which could enrich the therapeutic arsenal to manage cardiac diseases.

Attività di ricerca

MET ACTIVATING ANTIBODIES AS THERAPEUTIC TOOLS AGAINST CARDIAC HYPOXIC DAMAGE

Cardiac ischaemia activates the hypoxia-inducible factors (HIF) pathway, which induces a transcription program regulating different cellular processes, among which angiogenesis, survival, metabolism and cell migration. Although the acute hypoxic response enhances cell survival and promotes adaptation to low oxygen environment, chronic or extreme hypoxic conditions initiate cell death program(s). Growth factors are reported to act as the survival factors released during myocardial ischaemia. In particular, HGF has been proposed as a modulator of cardiac repair in experimental myocardial infarction, which protects cardiomyocytes from apoptosis. However, the mechanism(s) through which HGF/Met system changes the ischaemia-induced death signals into survival signals are not known. In this project we want to test the cardioprotective function of HGF and Met activating antibodies against hypoxic injury. Such agents could ameliorate the current therapies for myocardial infarction. This study has allowed to publish a scientific paper: Gallo S. et al. Cell Death Dis. 2014, 5: e1185. It has been funded by the FPO (Fondazione del Piemonte per l’Oncologia).

 

IDENTIFICATION OF NEW MOLECULES FOR CARDIOPROTECTION AGAINST ANTHRACYCLINE CARDIOTOXICITY.

Anthracyclines (Ant) are the most widely used anti-tumoral drugs. Unfortunately, chronic administration of Ant induces cardiotoxicity (CTX) due to their inability to discriminate tumor from normal cardiac cells. CTX can be manifested already during the chemotherapeutic treatment, but also immediately or even years after the end of the therapy. Therefore, it is necessary to develop new cardioprotective molecules in order to ameliorate and make safer anti-tumoral treatments. Since the molecular mechanisms involved in Ant-mediated CTX include oxidative stress, anti-oxidant and prosurvival agents seem to be attractive candidates. For this purpose, in this project, the cardioprotective activity of growth factor mimetics, polyphenols, ranolazine and other antioxidant agents will be tested in vitro and in vivo.

 

IDENTIFICATION OF CIRCULATING miRNAs AS NEW PROGNOSTIC BIOMARKERS FOR EVOLUTION OF CHRONIC ADVANCED HEART FAILURE.

Population aging leads to an increase in heart disease which results in chronic advanced heart failure (HF), refractory to pharmacological therapies. Awaiting heart transplantation, LVAD is the only "destination therapy" for the majority of patients and is applied only to those in the more severe stage. The goal of the project is to analyze expression profiles of miRNAs in serum of controls and patients with advanced chronic HF to identify a set of miRNAs correlated with the stage of the disease and predictive of the development of major cardiac events. Bioinformatic analysis of the expression data will allow us to obtain information about the molecular processes involved, better classify the degree of disease aggravation risk and select in advance frail patients for an early therapeutic intervention. The research is funded by the Fondazione CRT.

Gallo S., Sala V., Gatti S., Crepaldi T. “Cellular and molecular mechanisms of HGF/Met in the cardiovascular system.” Clin Sci, 2015; 129(12): 1173-1193.

Sala V.*, Gallo S.*, Gatti S., Vigna E., Ponzetto A., Crepaldi T. “Anti-differentiation effect of oncogenic Met receptor in terminally-differentiated myotubes”, Biomedicines, 2015; 3: 124-137. *These authors contributed equally to this work.

Gallo S., Sala V., Gatti S., Crepaldi T. “HGF/Met Axis in Heart Function and Cardioprotection.”, Biomedicines, 2014; 2: 247-262.

Gallo S., Gatti S., Sala V., Comoglio P.M. and Crepaldi T. “HGF/Met axis has anti-apoptotic and anti-autophagic function in hypoxic cardiac injury”, Receptor Clin Invest,2014; 1: 292-294.

Gallo S., Gatti S., Sala V., Albano R., Costelli P., Casanova E., Comoglio P.M. and Crepaldi T. “Agonist antibodies activating the Met receptor protect cardiomyoblasts from cobalt chloride-induced apoptosis and autophagy”, Cell Death Dis, 2014, 5: e1185.

Sala V., Bergerone S., Gatti S., Gallo S., Ponzetto A., Ponzetto C., Crepaldi T. “MicroRNAs in myocardial ischemia: identifying new targets and tools for treating heart disease. New frontiers for miR-medicine.”,  Cell Mol Life Sci,2014, 71(8):1439-52.

Gatti S., Leo C., Gallo S., Sala V., Bucci E. , Natale M., Cantarella D., Medico E., Crepaldi T. “Gene expression profiling of HGF/Met activation in neonatal mouse heart.”, Transgenic Res, 2013, 22(3): 579-93.

Sala V., Gallo S., Leo C., Gatti S., Gelb BD, Crepaldi T. “Signaling to cardiac hypertrophy: insight from human and mouse RASopathies.”, Mol Med, 2012, 18: 938-947.

Riess I., Sala V., Leo C., Demaria M., Gatti S., Gallo S., Fitou A., Boero O., Levi R., Cuccovillo I., Molla F., De Angelis N., Staszewsky L., Latini R., Crepaldi T. “A mouse model for spatial and temporal expression of HGF in the heart”, Transgenic Res, 2011, 20(6): 1203-1216. 

 Gallo S., Gatti S., Bonzano A., Sala V., Comoglio P.M. and Crepaldi T. “Met Activation for Cardioprotection against Anthracycline Cardiotoxicity”. XX National SIRC Congress (Società Italiana di Ricerche Cardiovascolari). Imola, Italy. 26-28 November 2015.

Gallo S., Gatti S., Bonzano A., Sala V., Comoglio P.M. and Crepaldi T. “Met Activation for Cardioprotection against Anthracycline Cardiotoxicity”. D -day 2015, Doctoral school in Life and Health Sciences, University of Turin.

Gallo S., Gatti S., Bonzano A., Sala V., Comoglio P.M. and Crepaldi T. “Met Activation for Cardioprotection against Anthracycline Cardiotoxicity”. 2015 International Conference Molecular Oncology “From Signal Transduction to Cancer Precision Medicine”. Candiolo Cancer Institute, Turin, Italy. 6-7 Giugno 2014.

  Gallo S., Gatti S., Sala V., Costelli P., Albano R., Comoglio P. and Crepaldi T. “HGF receptor agonists protect cardiomyocytes from Cocl2-induced cell injury”. Frontiers in Regenerative Medicine. Molecular Biotechnology Center (MBC). Turin, Italy. 18-20 February 2015.

 Gallo S., Gatti S., Sala V., Comoglio P.M. and Crepaldi T. “HGF/Met axis in Cancer Therapy Cardiotoxicity and Cardioprotection”.2014 International Conference Molecular Clinical Oncology “Precision Medicine”. Candiolo, Turin, Italy. 4-5 October 2014.

Gallo S., Gatti S., Sala V., Costelli P., Albano R., Comoglio P. and Crepaldi T. “HGF Receptor Agonists protect cardiomyocytes from CoCl2-induced cell injury”. EMC 2013 42ND European Muscle Conference. Amsterdam, The Netherlands. 21-26 September 2013.

Sala V, Gallo S, Gatti S, Morello M, Leo C, Cantarella D, Medico E, Ponzetto C, Ponzetto A, Crepaldi T. “Sustained met signalling in the heart leads to cardiac compensated hypertrophy and remodelling, which evolve into congestive heart failure”. EMC 2013 42ND European Muscle Conference. Amsterdam, The Netherlands. 21-26 September 2013.

Gallo S., Gatti S., Sala V., Costelli P., Albano R., Comoglio P. and Crepaldi T. “HGF Receptor Agonists protect cardiomyocytes from CoCl2-induced cell injury”. Recent advances in cardiac repair: from stem cells to biomaterials and small molecules. Molecular Biotechnology Center (MBC). Turin, Italy. 20-21 June 2013.

Sala V, Gallo S, Gatti S, Morello M, Leo C, Cantarella D, Medico E, Ponzetto C, Ponzetto A, Crepaldi T. “Sustained met signalling in the heart leads to cardiac compensated hypertrophy and remodelling, which evolve into congestive heart failure”. Recent advances in cardiac repair: from stem cells to biomaterials and small molecules. Molecular Biotechnology Center (MBC). Turin, Italy. 20-21 June 2013.

Gatti S., Leo C., Gallo S., Sala V., Bucci E., Poli A., Cantarella D., Medico E., Crepaldi T. “Analysis of molecular prolfiling data to understand the whole-genome effects of HGF stimulus in the heart”. Arturo Falaschi Conference Series on Molecular Medicine – Frontiers in Cardiac and Vascular Regeneration. Trieste, Italy. 30 May – 2 June 2012.

Gallo S., Leo C., Sala V., Gatti S., Crepaldi T. “HGF-mediated modulation of Connexin43 in cardiac cells”.  36th FEBS Congress. Torino, Italy. 25-30 June 2011.

Leo C., Sala V., Morello M., Riess I., Gallo S., Gatti S., Crepaldi T. “Evidences for aberrant met signalling involvement in the pathogenesis of heart disease”. XVII Congresso Nazionale della Società Italiana di Ricerche Cardiovascolari. Imola, Italy. 7-9 October 2010.

V. Sala, S. Gatti, C. Leo, M. Morello, I. Riess, S. Gallo, E. Bucci, D. Cantarella, E. Medico, S. Schiaffino, T. Crepaldi "HGF/c-Met role in postnatal heart development”. European Muscle Conference 2010. Abano Terme, Italy. 11-15 September 2010.

Crepaldi T., Gatti S., Leo C., Sala V., Riess I., Gallo S., Bucci E., Cantarella D., Medico E. “Gene profiling in HGF-stimulated early postnatal heart”. Weinstein Cardiovascular Development Conference. Amsterdam, TheNetherlands. 20-22 May 2010.

Gatti S., Leo C., Sala V., Riess I., Gallo S., Bucci E., Cantarella D., Medico E., Crepaldi T. “Gene profiling in HGF-stimulated early postnatal heart”. Research day of the Dept. of Anatomy, Pharmacology and Forensic Medicine.Turin, Italy. 6 May 2010.

 

Sala V., Leo C., Morello M., Gallo S., Gatti S., Riess I., Crepaldi T. “Evidences for aberrant Met signalling involvement in the pathogenesis of heart disease”. Research day of the Dept. of Anatomy, Pharmacology and Forensic Medicine.Turin, Italy. 6 May 2010.

XX National SIRC Congress (Società Italiana di Ricerche Cardiovascolari). Imola, Italy. 26-28 November 2015.

2015 International Conference Molecular Oncology “From Signal Transduction to Cancer Precision Medicine”. Candiolo Cancer Institute, Turin, Italy. 6-7 Giugno 2014.

Frontiers in Regenerative Medicine. Molecular Biotechnology Center (MBC). Turin, Italy. 18-20 February 2015.

Ultimo aggiornamento: 09/10/2019 11:18
Non cliccare qui!