Overview

Research Highlighted by Duke MedicineNews!

Bias calculator (using efficacies and potencies)

The research of the Rajagopal lab focuses on signaling at the intersection of inflammation and vascular diseases such as pulmonary arterial hypertension (PAH). PAH is a disease of the pulmonary arterioles that results in right heart failure and most of its treatments target signaling by G protein-coupled receptors (GPCRs). Our lab focuses on the signaling mechanisms of GPCRs, such as chemokine receptors that regulate immune function in PAH, and novel paradigms for their regulation in health and disease. We use multiple approaches to probe these signaling mechanisms, including in-house pharmacological assays, advanced phosphoproteomics and single cell RNA sequencing.

G protein-coupled receptors (GPCRs) are the most common transmembrane receptors in the human genome (over 800 members) and are some of the most sucessful targets for drug therapies. While it has been known for some time that these receptors signal through multiple downstream effectors (such as heterotrimeric G proteins and multifunctional beta arrestin adapter proteins), over the past decade it has been better appreciated that these receptors are capable of signaling with different efficacies to these effectors, a phenomenon referred to as “biased agonism”. Ligands can be biased, by activating different pathways from one another, and receptors can be biased, by signaling to a limited number of pathways that are normally available to them. Moreover, this phenomenon also appears to be common to other transmembrane and nuclear receptors. While a growing number of biased agonists acting at multiple receptors have been identified, there is still little known regarding the mechanisms underlying biased signaling and its physiologic impact.

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