Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and usually lethal lung disorder of unknown aetiology. At present there are no proven therapies for IPF. Current research indicates that the mechanisms driving IPF reflect abnormal, deregulated wound healing within the lung, involving increased activity and possibly exaggerated responses by a spectrum of pro-inflammatory and pro-fibrogenic factors. In order to understand the molecular basis for pulmonary fibrosis in more detail, we have analyzed the transcriptional profiles of disease progression in an animal model of Bleomycin-induced pulmonary inflammation and fibrosis and compared them with all publicly available information. Following computational data analysis, the most informative genes were/are further validated both at the RNA and protein level. Prediction of function and involvement in disease was/is then evaluated in vitro in immortalized lung epithelial and/or fibroblast cell lines and/or in vivo through genetic modification of mice. In this context we have recently shown that 1) soluble TNF secretion from apoptosing alveolar epithelial cells is a prerequisite for the development of the modelled disease, 2) Hypoxia inducible factor 1a (Hif-1a) is overexpressed in the hyperplastic epithelium of IPF patients, colocalizing with various apoptotic markers and 3) gelsolin-mediated epithelial apoptosis and neutrophil migration are necessary for disease development. Ongoing projects investigating the development of pulmonary inflammation and fibrosis are focusing 1) on the role of ATX and LPA signalling in lung pathophysiology, 2) on the role of NF-κB in epithelial apoptosis upon lung injury and 3) on the genetic dissection of the potential role of Hif-1a in epithelial apoptosis and lung homeostasis.

The role of ATX and LPA signalling in embryonic development, pathophysiology and cancer

Lysophosphatidic acid (LPA) is a bioactive lysophospholipid that evokes a great variety of cellular responses in almost all cell types, including cell migration, proliferation and survival. LPA signaling has been implicated in wound healing, embryonic development and tumor progression. LPA is produced extracellularly by a secreted lysophospholipase D, named autotaxin (ATX), whose levels were found upregulated in our expression profiling of chronic inflammatory diseases such as rheumatoid arthritis and pulmonary fibrosis. To elucidate the importance of ATX in embryonic development, pathophysiology and cancer we have generated a conditional ATX knock-out mouse. The complete knock out is embryonically lethal (E9.5), exhibiting severe malformations of the neural system and aberrant angiogenesis. Current projects are exploring the role of ATX and LPA signalling in the pathophysiology of chronic inflammatory and neurodegenerative diseases, as well as in various forms of cancer.

Research and development of expression profiling through DNA microarrays

Expression profiling, the expression levels of thousand of genes, by DNA microarrays is a powerful tool for biologists, mathematicians and computer scientists in their attempt to decipher the complex organization of biological phenomena. The expression profile of any given cell, to any given status or response, constitutes a molecular fingerprint which could help to discriminate between malignant and benign, active or quiescent, resting or infected.
Our laboratory has pioneered the establishment and development of this exciting technology in Greece, and is currently supervising the expression profiling unit of BSRC Fleming, offering services to academic and research centres, as well as the private sector, in the context of academic collaborations, participation in research networks, and/or contracted services. Visit the Expression Profiling Unit website.

Mouse informatics resources: Creation, curation, coordination and interoperability

Much of the current effort in functional genomics, and our understanding of the biology of human disease, is underpinned by informatics infrastructures served by the scattered collection of relevant databases which exists in Europe. This infrastructure is essential for the support of a European Research Area in functional genomics and failure to integrate and sustain these databases will have deleterious effects on research competitiveness. In this context, we have created 1) The MUGEN mouse database (MMdb), a database of murine models of immune processes and immunological diseases aiming to share and publicize information on mouse strain characteristics and availability and 2) the Fleming mouse database, listing all locally available mouse strains. Moreover, in the context of a European commission co-ordination action grant, we are exploring database interoperability and sustainability, having organized a series of scientific meetings and produced a number of reports and scientific papers. Moreover we have created the Mouse Resource Browser (MRB), a database for searching and retrieving information about online mouse resources, as well as their interoperability mode (web services, dumps). Finally we have created TgDb (soon to be renamed to creZOO), a database of all available transgenic mouse lines expressing the Cre recombinase, an essential tool to exploit the increasing availability of targeted conditional alleles in the mouse produced by the International Knockout Mouse Consortium. The project was recently funded by the European commission to be fully curated and to integrate with Mouse Genome Informatics (MGI at Jackson labs) and the Ensembl mouse genome browser (at the EMBL European Bioinformatics Institute) among others. Visit the BioIT website.