LinkedIn: https://be.linkedin.com/in/gilles-vanderstocken-10247827

Validation of new drug candidates to treat chronic obstructive pulmonary disease identified by connectivity map analyses of mouse and human lung gene expression

Smoking is the main risk factor for chronic obstructive pulmonary disease (COPD), an inflammatory lung disorder characterized by progressive and largely irreversible airway obstruction. The purpose of this project is to use a computational discovery approach to identify novel drug candidates for COPD. This new approach utilizes lung genome expression profiles to compute in silico potential drug targets. Drug candidates will next be validated in relevant experimental model of COPD.

Why is the research project/program important?

While smoking prevalence has been decreasing, the number of smokers globally increased significantly because of population growth. To date, tobacco sale is at an all time high with an increase in over 1 trillion cigarettes sold yearly since the 1980. Smoking is the main risk factor for COPD and accounts for as many as 8 out of 10 COPD-related deaths. COPD remains a major health challenge worldwide, as existing pharmacologic interventions have been ineffective at preventing the disease. In this project, we use a new bioinformatics approach for drug discovery. Connectivity Map is a cutting-edge computer-based approach for effective drug discovery. With an aging population and increasing numbers of people smoking globally, such research is critically required.

What was the result of the project and what impact will it have?

The Connectivity Map analysis yielded 14 novel drug candidates conserved in mice and humans. Amongst them, our data suggest that a flavonoid, widely distributed in common fruits and vegetables (tomato, strawberry, apple, broccoli, and onions) and beverages such as tea and coffee may be an effective to improve COPD management. This study provides rationale to investigate further this flavonoid in experimental models.

Publications

Published

Shen, P., Morissette, M., Vanderstocken, G., Gao, Y., Hassan, M., Roos, A., … Stampfli, M. (2016). Cigarette smoke attenuates the nasal host response to Streptococcus pneumoniae and predisposes to invasive pneumococcal disease in mice. Infection and Immunity, 01504-15. [Epub ahead of print].

Jolly, L., Stavrou, A., Vanderstoken, G., Meliopoulos, V. A., Habgood, A., Tatler, A. L., … Jenkins, G. (2014). Influenza Promotes Collagen Deposition via αvβ6 Integrin-mediated Transforming Growth Factor β Activation. The Journal of Biological Chemistry, 289(51), 35246–63.

Vanderstocken, G., van de Paar, E., Robaye, B., di Pietrantonio, L., Bondue, B., Boeynaems, J. M., … Communi, D. (2012). Protective Role of P2Y2 Receptor against Lung Infection Induced by Pneumonia Virus of Mice. PLoS ONE, 7(11):e50385.

Brohée, S., Janky, R., Abdel-Sater, F., Vanderstocken, G., André, B., & Van Helden, J. (2011). Unraveling networks of co-regulated genes on the sole basis of genome sequences. Nucleic Acids Research, 39(15), 6340–6358.

Vanderstocken, G., Bondue, B., Horckmans, M., Di Pietrantonio, L., Robaye, B., Boeynaems, J.-M., & Communi, D. (2010). P2Y2 receptor regulates VCAM-1 membrane and soluble forms and eosinophil accumulation during lung inflammation. Journal of Immunology, 185(6), 3702–3707.

Brohée, S., Faust, K., Lima-Mendez, G., Vanderstocken, G., & van Helden, J. (2008). Network Analysis Tools: from biological networks to clusters and pathways. Nature Protocols, 3(10), 1616–1629.

Brohée, S., Faust, K., Lima-Mendez, G., Sand, O., Janky, R., Vanderstocken, G., … van Helden, J. (2008). NeAT: a toolbox for the analysis of biological networks, clusters, classes and pathways. Nucleic Acids Research, 36 (Web Server issue):W444-51.

In press

Dvorkin-Gheva, A.*, Vanderstocken, G.*, Yildirim, A.Ö., Brandsma, C-A., Obeidat, M., Bossé Y., … Stampfli, M. R. Total particulate matter concentration skews cigarette smoke’s gene expression profile. European Respiratory Journal - open research. *These authors contributed equally.

Acknowledgements

Boeckstaens, M., Llinares, E., Van Vooren, P., & Marini, A. M. (2014). The TORC1 effector kinase Npr1 fine tunes the inherent activity of the Mep2 ammonium transport protein. Nature Communications, 5, 3101.