Progetto Cariplo

  • FONDAZIONE CARIPLO - BANDO 2011 PER LA RICERCA IN CAMPO BIOMEDICO
  • Molecular mechanisms of Helicobacter pylori interplay with epithelial and non-epithelial cells of human gastric mucosa leading to immune-inflammatory response and carcinogenesis: a combined in vitro and in vivo study

Helicobacter pylori (HP) is a Gram-negative bacterium that specifically colonizes the gastric mucosa of about half of the world’s population, thus being the most common bacterial infection worldwide. Typically acquired during childhood, the infection can persist in the gastric ecosystem throughout the life span of the host, if untreated. Colonization of the stomach by HP causes chronic gastritis that can evolve into more severe diseases, such as atrophic gastritis, peptic ulcer, lymphoma of the mucosa-associated  lymphoid tissue or gastric adenocarcinoma. HP infection is the strongest known risk factor for gastrointestinal malignancies that arise within the stomach: in 1994 the WHO classified it as a definite, class I carcinogen. Gastric cancer is the fourth most common cancer, the second leading cause of cancer related death, and the 14th most common cause of death overall worldwide. Indeed, HP infection and related diseases cause a highest cost in terms of either human suffering and death or social expenses for medical care. In spite of about 30 years of active research (since 1983, when HP has been identified and its causative role in gastric diseases demonstrated), many key questions are still open about the molecular mechanisms by which this bacterium interacts with epithelial and non-epithelial cells of the human gastric mucosa subverting their functions so as to allow the bacterium to achieve its paramount goal of a successful and persistent colonization. The present project is devoted to investigate the yet largely unknown molecular mechanisms of the crosstalk between HP and the different cells (epithelial and non-epithelial) of human gastric mucosa, which is the result of millennia of co-evolution of the pathogen and its human host.

In particular, the present project is aimed to shed light on the following “black holes”: a) processing of HP and of its main products/virulence factors by gastric epithelial cells and, in particular, the molecular mechanisms of HP-induced genesis of the novel proteasome-enriched cytoplasmic structure (PaCS) that we have recently identified and that, according to our most recent data, may have a significant role in the carcinogenic cascade both in infectious and non-infectious diseases, b) molecular mechanisms by which the HP virulence factor CagA interacts with human gastric epithelium and acts together with the VacA toxin on endocytosis and signalling of EGF receptor, which plays a major role in the carcinogenic cascade, c) modulation of gastric epithelial production of cytokines, chemokines, and proinflammatory mediators during HP infection, d) molecular mechanisms of the failure of host response to the infection and, in particular, the putative role of myeloid-derived suppressor cells (MDSC) in such a scenario, and e)

molecular mechanisms by which, in infected patients, HP triggers a Th17 response which may lead to gastric autoimmune diseases. Both the research teams involved in the present project have 20 years of experience in studying the molecular mechanisms of HP-induced gastric damage and their components are internationally-recognized as leading scientists in the field. For each of the specific aims proposed preliminary data have already been acquired. Worth noting, for the first time a study on molecular mechanisms of HP-induced diseases will exploit a combined in vivo, ex vivo and in vitro experimental approach, thus bridging the gap between basic research and clinical observations. This will allow guaranties about the clinical counterpart and biological plausibility of the results obtained. The final objectives of the research project can be achieved only with the convergence of different technical and methodological approaches and with their mutual tuning. Indeed, the proposed study will benefit of the following multidisciplinary expertise of the contributing teams:

 1) gastroenterology, 2) pathologic anatomy; 3) molecular cell biology, 4) biochemistry, 5) immunology, 6) microbiology, 7) advanced light and electron microscopy.

In conclusion, several hotly debated topics will be investigated by an experienced research network through innovative experimental approaches and methodologies, thus with the possibility to finally shed light on important “black holes” in the current knowledge of molecular cross-talk between HP and human stomach. A definite answer to such questions not only will allow a better comprehension of the molecular basis by which the most common bacterial infection worldwide may lead to major human diseases but also could help in designing new therapeutic approaches (including immunotherapies) in diseases not necessarily related to HP infection.

Scientific responsible - partner 1

Team members - partner 1

Keywords

helicobacter pylori, gastric cancer,gastric epithelium, host immune response

Partnership

  • Università degli Studi di Pavia - Dipartimento di Fisiologia (capofila) - prof. Vittorio Ricci
  • Università degli studi di Padova - Dipartimento di Biologia, responsabile scientifico, Prof.ssa Marina de Bernard - PARTNER 1