Project 11

Peter Valent, Dept. of Medicine I, Medical University of Vienna.

Project 11: Identification of novel markers and therapeutic-targets in IgE-R cross-linked mast cells and basophils

Peter Valent is an internationally renowned expert in the field of basophil and mast cell research who has published more than 460 papers, reviews and book contributions. Recently Valent has started to explore the signaling machinery of mast cells and basophils and asked whether combined targeting of one or more signaling cascades by RNAi or targeted drugs can block the secretory capacity and mediator production in mast cells and basophils in IgE-dependent reactions. In addition, he has recently established a series of novel human mast cell lines expressing functional IgE-R and/or KIT-activating mutations. These cell line models will be employed to screen for and validate novel potential targets. The specific aims in the project are to identify new potential markers and targets in IgE-R-cross-linked or/and cytokine-exposed mast cells and basophils by screen profiling approaches, to determine the role of gene mutations or polymorphisms in releasability and activation patterns in mast cells, and to identify relevant cooperating signalling pathways. Further aims are to explore drug-target interactions and the effects of various targeted drugs on mediator- and cytokine production and secretion as well as mast cell survival. Long term aims are to establish novel markers and assays measuring allergic reactions at the effector cell level using standardized human cell line models, and to identify drug combinations that interfere with multiple activation pathways and thereby synergize with each other to produce major inhibitory effects on mediator production and secretion. Another long term goal is to identify subgroups of patients and to develop individualized therapies based on genetic background factors, somatic mutations like KIT-activating mutations, and co-morbidities. The effects of various drugs and drug combinations on mediator release and cell activation will be examined using primary cells from patients with IgE-dependent allergies, mast cell activation syndromes, primary mast cell disorders (mastocytosis), and basophil-related disorders. In addition, he will employ various human mast cell lines, including newly generated cell lines expressing functional IgE-R or/and KIT-activating mutations. The results obtained in this project should provide a solid basis for the development of new improved diagnostic tools and new pharmacologic concepts in disorders in which IgE-dependent mast cell- and/or basophil activation play a predominant pathogenetic role.

Publications:

Akin, C., P. Valent, and D. D. Metcalfe. 2010. Mast cell activation syndrome: Proposed diagnostic criteria. J. Allergy Clin. Immunol. 126: 1099-1104 e1094.

Valent, P., C. Akin, M. Arock, K. Brockow, J. H. Butterfield, M. C. Carter, M. Castells, L. Escribano, K. Hartmann, P. Lieberman, B. Nedoszytko, A. Orfao, L. B. Schwartz, K. Sotlar, W. R. Sperr, M. Triggiani, R. Valenta, H. P. Horny, and D. D. Metcalfe. 2012. Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal. Int. Arch. Allergy Immunol. 157: 215-225.

Blatt, K., H. Herrmann, I. Mirkina, E. Hadzijusufovic, B. Peter, S. Strommer, G. Hoermann, M. Mayerhofer, K. Hoetzenecker, W. Klepetko, V. Ghanim, K. Marth, T. Fureder, V. Wacheck, R. Valenta, and P. Valent. 2012. The PI3-kinase/mTOR-targeting drug NVP-BEZ235 inhibits growth and IgE-dependent activation of human mast cells and basophils. PLoS One. 7: e29925.

Hadzijusufovic, E., B. Peter, H. Herrmann, T. Rulicke, S. Cerny-Reiterer, K. Schuch, L. Kenner, T. Thaiwong, V. Yuzbasiyan-Gurkan, W. F. Pickl, M. Willmann, and P. Valent. 2012. NI-1: a novel canine mastocytoma model for studying drug resistance and IgER-dependent mast cell activation. Allergy. 67: 858-868.

Valent, P. 2013. Mast cell activation syndromes: definition and classification. Allergy. doi: 10.111/all.12126