Grant: Project Grant

Pulmonary Arterial Hypertension (PAH) is a serious disease where the blood pressure in the arteries of the lungs becomes too high. This puts extra strain on the heart, eventually leading to heart failure, which can be life-threatening. New research suggests that our body's internal clock, called the circadian rhythm, could play an important role in PAH. The circadian rhythm controls many of our body's processes, like sleep, metabolism, and inflammation, and is guided by proteins that act like clocks inside our cells. One of these proteins, called Rev-Erba, has been linked to several of the processes disrupted in PAH. This research aims to understand how Rev-Erba might be involved in PAH and whether it could be a target for new treatments. In the first part of this research, we want to find out if the circadian rhythm is disrupted in PAH patients and animal models. We will study cells from the lungs of people with PAH and compare them to healthy cells, focusing on Rev-Erba and how it might be malfunctioning in PAH. Next, we will explore how Rev-Erba affects the development of PAH. Since Rev-Erba helps control metabolism, the cell cycle, and inflammation processes that are often out of balance in PAH we want to see how its malfunction contributes to the disease. We will test this by changing Rev-Erba levels in cells using different techniques and then studying how the cells behave. Finally, we will test a drug called SR9011 that can activate Rev-Erba. We will see if this drug can help treat PAH in animal and human lung tissue. By understanding how SR9011 works, we hope to discover if it can improve PAH and lead to new treatments. The goal of this research is to better understand how our body's internal clock affects PAH and whether Rev-Erba can be targeted to help treat the disease. If successful, this research could lead to new therapies that are specifically timed to work with the body's natural rhythms, offering a promising new approach to treating PAH.