Determining the molecular mechanisms that underlie the function of vascular ion channels and identifying new ion channel targets and specific drug compounds with the goal of modulating blood vessel function for therapeutic benefit.
High blood pressure (hypertension) is a health problem that affects nearly one billion people or ~26% of the adult population worldwide. Untreated, hypertension results in premature death due to consequential damage to major organs like the brain, heart and kidneys. Blood pressure is determined by cardiac output and by the resistance to blood flow within peripheral blood vessels, which is determined by the degree of contraction of vascular smooth muscle. Pivotal to contractile processes are vascular ion channels; those found in smooth muscle determine the electrical impulses that directly control muscle cell contraction, while those in vascular endothelial cells participate in the release of chemical factors that, in turn, also regulate vascular muscle tone. Thus, vascular ion channels represent prime targets for novel therapies with which to treat hypertension and related conditions.
My research aims are two-fold: 1) to determine the molecular mechanisms that underlie the function of vascular ion channels and 2) to identify new ion channel targets and specific drug compounds with the goal of modulating blood vessel function for therapeutic benefit.
To achieve these aims the lab takes an integrative approach, with investigations at the level of molecules, cells, tissues and the whole organism, using a combination of experimental and theoretical approaches.
Our current efforts are focused on calcium-activated chloride channels (CaCCs). In vascular smooth muscle, CaCCs play a key role in coupling agonist-induced Ca2+ release with membrane depolarisation and resistance to blood flow. Although long-proposed as a potential target for treating hypertension, their molecular identity has been unknown for a long time. We recently uncovered TMEM16A/Anoctamin1 protein as the prime CaCC in vascular smooth muscle. We are interested in identifying the domains of the TMEM16A channel that are responsible for its functional properties and in elucidating how drug binding affects channel activity. We also use animal models and mathematical modelling to determine the precise role of CaCC channels in the various circulations. Our work may facilitate the development of novel drugs for the treatment of a range of cardiovascular diseases.