Looking at RNA to get to the heart of cardiovascular disease

Yale will play a vital part in an expansive study on the role of long non-coding RNAs and microRNAs (miRNAs) in cardiovascular disease, thanks to a $6 million grant from the Paris-based Fondation Leducq.

The five-year grant, awarded under the foundation’s Transatlantic Networks of Excellence Program (TNEP), enables a transatlantic collaboration among international leaders in cardiovascular RNA biology with complementary research interests. The School of Medicine’s William C. Sessa, Ph.D., the Alfred Gilman Professor of Pharmacology and professor of medicine, will lead the American “half” of the project, as U.S. coordinator.

RNA is a family of biological molecules involved in the coding, decoding, regulation, and expression of genes. Prior to the last decade, its role in cardiovascular disease had been largely unexplored.

The project’s goal—to elucidate the role of non-coding and miRNAs in cardiovascular disease—furthers the foundation’s mission of improving human health through international efforts to combat cardiovascular and neurovascular disease. Its core aims include creating a “data bank”: an annotated list of the long non-coding RNAs expressed in cardiovascular tissues, to be made available as a resource for scientists in the international cardiovascular community. Another aim is to better understand how circulating miRNAs function: whether they cause disease, or are merely biomarkers—indicators, but not necessarily the cause, of conditions or processes.

Sessa’s research focuses on the vascular endothelium, cells that line all blood vessels, and on the factors that can cause dysregulation of the endothelium and contribute to cardiovascular disease. His lab has been at the fore in describing the miRNA profile of vascular cells. In 2007 Sessa and colleagues published a study showing that miRNAs played a vital functional role in blood vessels. More recently, his group has shed light on the connection between miRNA-29 and the gene ELN. ELN codes for a protein called tropoelastin, the precursor of the elastin that gives blood vessels their elasticity and helps them to open and close in response to the cardiac cycle.

Sessa’s part in the multi-pronged project is to identify important mi-RNAs in endothelial cells and smooth muscle cells, which compose the bulk of vessel walls, as well as to investigate the role of miRNAs that influence either vascular remodeling in aneurysm formation or how blood vessels are made.

The project was conceived as a way to combine diverse expertise and complementary research interests. “My collaborators are all people that I admired scientifically,” says Sessa, also director of the medical school’s Vascular Biology and Therapeutics Program. “To be able to work with them without competing against them is refreshing.”

The grant joins four European labs with three in the U.S., including two at Yale: Sessa’s and that of Carlos Fernández-Hernando, Ph.D., associate professor of comparative medicine. It fosters an exchange of students and postdoctoral fellows, who will travel to partner institutions to gain experience with new research and technologies. The project’s European coordinator is Thomas Thum, M.D., Ph.D., of Hannover Medical School in Germany.

The $6 million TNEP grant is the third such grant awarded by the foundation to School of Medicine scientists. In 2007 the foundation supported a project involving Yale’s Richard P. Lifton, M.D., Ph.D., chair and Sterling Professor of Genetics and a Howard Hughes Medical Institute investigator, and the late Steven C. Hebert, M.D., then chair and C.N.H. Long Professor of Cellular and Molecular Physiology, aimed at pinpointing the kidney’s role in high blood pressure. In 2010 the foundation funded research involving Michael Simons, M.D., the Robert W. Berliner Professor of Medicine and professor of cell biology, and colleagues at the Yale Cardiovascular Research Center, on the link between metabolism and arteriogenesis—the process by which new arterial blood vessels form.

Jean and Sylviane Leducq established the Fondation Leducq in 1996 to support cardiovascular disease research. One of the foundation’s goals is to promote collaboration between researchers in North America and Europe. In 2004 it began to accept applications for its Transatlantic Networks of Excellence in Cardiovascular Research Program, and in 2011 the foundation opened the program to cardiovascular and neurovascular scientists worldwide. As of 2013, the foundation had awarded 39 Transatlantic Network grants, totaling more than $240 million, to hundreds of researchers in 18 countries.

Says Sessa, “It’s incredible to have non-federal sources of funding nowadays, considering the climate today for getting federal grants.”