Grant: Operating Grant

The cardiovascular system is affected by a variety of stimuli, many of which are peptidic in nature. In order to become active most peptidergic hormone precursors are submitted to cleavage by proteases. This permits the production of the bioactive peptide, which is later secreted from the cell. This peptide then interacts with cell-surface receptors enabling the hormone to transmit its signal to the cell, which in turn emits a response. Deregulation of these peptidergic and receptor systems often leads to diseases such as hypertension, heart failure and other cardiovascular-related pathologies. Recently, two new hormonal peptides, urotensin II (UII) and urotensin-related peptide (URP) and the receptor with which they interact have been identified in man. Not only is UII amongst the most vasoactive peptide known but recent evidence shows that it also acts as an important chemotactic factor, a substance that attracts cells of the immune system in situations of tissue injury or infection. A vital area of activity in biomedical research is the identification of structural determinants within proteins that dictate or regulate their interaction with other proteins. We propose an integrated, multidisciplinary and multi-laboratory project intended to examine various facets of these interactions using the UII system as a model. Specifically, we will identify those 'molecular signatures' that are responsible for proUII and proURP's recognition and cleavage by specific proteases. We will determine what are the important amino acids involved for the recognition and activation of the UT receptor by UII and URP. Finally we will explore a novel concept called collateral efficacy, a way in which a single receptor can behave differently depending on the type of ligand it interacts with. Our studies will have an important impact in understanding how peptide hormones are produced and how they can influence cardiovascular function by their interaction with their receptor.