Grant: Research Tools and Instruments - Category 1 (<$150,000)

Most of the drugs currently used as therapies (including beta-blockers in heart disease and multiple others) are directed against the largest family of cell surface receptors which transduce signals outside of the cell into activity inside the cell), the seven transmembrane receptors (7TM-Rs). These drugs target the site where endogenous compounds interact with the receptor. Unfortunately, all of these drugs produce significant side effects. This may be in part because the targetting of the ligand binding site is not specific enough to block only the desired effect. This is likely due to the nature of the receptor and how it actually transmits signals inside the cell. Also, it is now known that different receptors can associate together and form a new receptor entity.  Surprisingly, very little attention has been given to the way these receptors form to permit signalling and what brings specificity of signalling.We know that each receptor can be coupled to multiple signalling pathways and that specific proteins can regulate the activity of the receptor. How can we make drugs that are more specific and have less side effects? I want to identify the proteins that associate with the new receptor entities (receptor heterodimers) and understand how the protein partners can regulate the signals transmitted inside the cell. Once the partners are known, this will provide researchers new therapeutic targets that will complement current therapies, and possibly reduce drug adverse effects. My group will use a new technology I developped to identify unique and specific heterodimeric receptor partners. The new technique developped is among the first ones to allow specific identification of heterodimeric receptor partners.Adverse effects of current drugs are probably induced by receptor heterodimers. Understanding the way these receptors work will help reduce drug adverse effects and help researchers develop better therapies.