GPCR signaling in Pulmonary Hypertension
We are interested in studying the role of G protein-coupled receptor (GPCR) signaling in pulmonary arterial hypertension (PAH), a disease of blood vessels in the lungs that is characterized by endothelial cell apoptosis, smooth muscle cell proliferation and inflammation. The obliteration of pulmonary arterioles results in right heart failure. Even with our current treatments, 5 year mortality for this disease is still close to 50%.
GPCRs are the most common receptors in the human genome, with over 800 members. They share a common architecture ( seven transmembrane domains) and couple to heterotrimeric G proteins that regulate second messengers such as cAMP, IP3 and calcium. The majority of current treatments in PAH target signaling by GPCRs, most commonly the prostacyclin and type A endothelin receptors. We are interested in understanding how these and other receptors contribute to the pathophysiology and development of PAH.
The Chemokine Family as a Model System for Understanding Biased Agonism
We have found that an excellent model system for understanding the mechanism and physiologic effects of biased agonism is the chemokine family. The chemokine family consists of over 20 receptors and 50 ligands. These ligands, chemokines, play central roles in inflammation, atherosclerosis and development. There is significant promiscuity between chemokines and their receptors, and rather than being redundant in their activites, we have found that the majority of these chemokines function as biased agonists. We are currently studying the mechanisms underlying this bias and its physiologic effects.
Beta-Arrestin-Mediated Signaling by GPCRs
Beta-arrestins are ubiquitous adapters that regulate GPCR signaling, trafficking and desensitization. Although their ability to mediate signaling through kinases and other pathways has been appreciated for over a decade, the full spectrum of their activity is not fully appreciated, especially as it relates to their physiologic effects. We are interested in linking the pharmacology of these receptors to their intracellular targets and subsequent physiologic effects.
Understanding the Mechanisms Underlying Biased Agonism
Biased agonism is the ability of a receptor:ligand complex to selectively activate its downstream signaling pathways. For example, a biased ligand acting at a receptor could act as an agonist of one pathway (such as through heterotrimeric G proteins) while acting as an antagonist of another pathway (such as beta-arrestins) (see Figure below).
From a theoretical standpoint, we are interested in understanding how to best quantify biased agonism and understand the links between pharmacologic- and mechanistic-based models of receptor signaling.