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Molecular and pharmacology study of the transient receptor potential channel TRP...

Molecular and pharmacology study of the transient receptor potential channel TRPV1 The somatosensory system detects and integrates a large array of noxious stimuli of highly divergent nature. Members of the transient receptor potential (TRP) ion channel family play a pivotal role in the detection of innocuous an... ver más

31/08/2016

THE HEBREW UNIVERS...

100K€

Presupuesto del proyecto: 100K€

Líder del proyecto

THE HEBREW UNIVERSITY OF JERUSALEM No se ha especificado una descripción o un objeto social para esta compañía.

TRL 4-5

Fecha límite participación Sin fecha límite de participación.

Financiación concedida El organismo FP7 notifico la concesión del proyecto el día 2016-08-31 No tenemos la información de la convocatoria

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THE HEBREW UNIVERSITY OF JER...

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Líder del proyecto

THE HEBREW UNIVERSITY OF JERUSALEM No se ha especificado una descripción o un objeto social para esta compañía.

TRL 4-5

Presupuesto del proyecto 100K€

Fecha límite de participación Sin fecha límite de participación.

Descripción del proyecto The somatosensory system detects and integrates a large array of noxious stimuli of highly divergent nature. Members of the transient receptor potential (TRP) ion channel family play a pivotal role in the detection of innocuous and noxious stimuli, of both physical and chemical nature. Thus, elucidating the gating mechanisms of these channels is essential for our understanding of somatosensation and nociception. Taken the polymodal nature of those somatosensory TRP channels, our overall goal is to provide a comprehensive understanding of their activation mechanisms as evoked by various stimuli. TRPV1, a member of this family, detects a variety of pain-evoking molecules such as vanilloids (capsaicin), protons and animal peptide toxins. This activity is mediated by at least two distinct channel regions; each binds different set of activators. Despite its central role in pain perception, our knowledge of TRPV1 molecular mechanism of action is limited. Here, we propose to examine the stoichiometry and allosteric regulation of TRPV1 activation through its two distinct binding regions. Our working hypothesis is that because TRPV1 is required to detect and react to a large range of noxious stimuli, each of its ligand-binding regions evolved to induce a defined activation mechanism. We will use concatemeric rat TRPV1 harboring subunit-specific mutants, which will be expressed in heterologous systems. We will analyze for changes in TRPV1 activation by various ligands using specific electrophysiological assays designed to measure channel gating, combined with calcium imaging and biochemical assays. Overall, the proposed study will identify the allosteric regulatory mechanisms by which TRPV1 is activated through its distinct ligand-binding regions, mechanisms that ultimately underlie the detection of noxious stimuli and pain perception. In whole, this study will facilitate the rational design of analgesics drugs, specifically targeting ligand-binding sites on pain receptors.

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