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Abstract:
Hydrogen sulfide (H2S) is generated in mammalians from L-cysteine in a cell type- and tissue-specific manner, by cystathione-?²-synthase and cystathionine-?³-lyase. H2S participates in the regulation of nervous and cardiovascular system functions, cellular metabolism, and immune/inflammatory responses. In spite of recent advances in H2S biology, the molecular mechanisms through which H2S affects cell functions remain unexplored.
The aims of the proposed study are to:
- elucidate the molecular mechanisms of action of H2S in vascular endothelial and smooth muscle cells,
- analyze the contribution of H2S in disease processes and correlate H2S function with angiogenesis in diseased tissues, and
- generate novel pharmacological inhibitors of H2S production.
Our proposal is composed of 7 workpakages (WPs).
- WP1 concern the coordination of the project that involves 11 principle investigators from 5 universities and 2 research institutes.
- In WP2 we will investigate H2S signaling and correlate the molecular events with key endothelial and smooth muscle functions (cell survival, angiogenesis, permeability, relaxation).
- In WP3 will evaluate the role of endogenous H2S in the development of the vascular system using genetics-based approaches in zebrafish, and analyze H2S-dependent transcriptome changes during development of the vascular system using microarrays.
- WP4 will focus on the role of H2S in vascular permeability.
- In WP5 we will study the production of H2S during pathophysiological conditions and link it to changes in angiogenesis in 2 model systems. The role of H2S will be evaluated in angiogenesis and disease progression in experimental colitis; the role of H2S in pathological angiogenesis and altered contractility of the diaphragm will be tested during resistive breathing.
- In WP6 we will design, synthesize and evaluate novel H2S production inhibitors.
- WP7 consists of all the dissemination activities related to results obtained from our proposed studies.
