- Project Title
- Molecular Systems Biology Helicobacter pylori
- Project Type
- Nacional / Public
- Funding Body
- Funding Program
- CEB: 136 200,00
- Total: 159 000,00
- Universidade do Minho e Instituto de Patologia e Imunologia Molecular (IPATIMUP/UP)
- External link
Team Members - CEB
The discovery and culture of Helicobacter pylori has revolutionized the diagnosis and treatment of gastroduodenal diseases. Epidemiological studies have shown that more than half of the world adult population harbours this bacterium in their stomach, inducing chronic gastritis in all infected persons and causing severe disease in subgroups of patients, such as peptic ulcers, gastric cancer, and gastric lymphoma of the mucosa-associated lymphoid tissue.
Research studies have indicated that the virulence factors of H pylori include those allowing the bacterium to survive in the hostile environment of the gastric lumen, adaptive enzymes and proteins, and ability to adhere to gastric mucosal cells and mucus.
However, since peptic ulcer disease and gastric cancer occur in only a subset of individuals chronically infected with H pylori, both bacterial and host factors are presumed to contribute to this differential response. In vivo and in vitro studies have shown that H pylori infection causes inflammation of the gastric mucosa by increasing the production of several pro-inflammatory cytokines. H pylori infection also induces alterations in epithelial cell morphology and interferes with mechanisms that regulate epithelial cell turnover, including proliferation and apoptosis. Moreover, oxidative stress is observed in the gastric mucosa as a response to the infection. However, the efforts for uncovering the mechanisms associated with
H. pylori infection and the appearance of diseases in the host are only in its beginning, as the complexity of the process has become clear from the studies performed in the last few years.
The recent progress made in omics technologies allow to evaluate changes in the abundance of most of the proteins and metabolites in different conditions and to infer the molecular mechanisms associated to different cellular responses.
On the other hand, the availability of the genome sequence of this microorganism has allowed the construction of a genome-scale metabolic model accounting for 3411 ORFs. Genome-scale models, when complemented with regulatory information, can be used to predict the phenotype of an organism under different genetic and environmental conditions. Additionally, the presence /absence of both proteins and metabolites under specific conditions can be predicted by such models. Therefore, for the particular case of H. pylori, metabolic models can be used to understand the molecular factors of the microorganism that are likely to interact
with the host and cause diseases. Additionally, these models can pinpoint molecular targets that can be used to design drugs able to inactivate the bacteria.
Nevertheless, it is clear that the quality of the predictions obtained with a given model is closely associated with its quality. The lack of information regarding metabolism and physiology of H. pylori hampers the development of a more accurate model, a fact that can
be overcome by the conduction of in vitro experiments where state-of-the art metabolite measurement techniques are used, together with proteomics analyses.
Under this scope, the present proposal aims at contributing to uncover the mechanisms of H. pylori that are relevant for the development of diseases in the host. For that purpose, molecular systems biology approaches will be used, namely the construction of a genome-scale regulatory and metabolic model of H. pylori and its use for simulating the icroorganism’s behaviour. The model will be validated mainly by performing metabolomics and proteomics experiments to H. pylori cultures. In order to perform such measurements and allow model construction, it will be necessary to be able to cultivate H. pylori under controlled conditions, a task that so far has not been achieved. Additionally, and after co-culturing H. pylori with a gastric host cell line, bacterial proteomic profiles will be evaluated.