It is rare for science to identify one key protein that determines a cell’s behavior in health and disease. KLF2 is one such protein. Among other functions, “it is the principal transcriptional pathway that keeps your arteries open and healthy,” says Martin A. Schwartz, PhD, Robert W. Berliner Professor of Medicine (Cardiology) and professor of biomedical engineering and of cell biology. Because it performs this essential role, Schwartz takes particular interest in anomalies in KLF2 expression that underlie multiple vascular diseases.
Fondation Leducq’s Transatlantic Networks of Excellence program has awarded Schwartz and a network of five other researchers, from North America and Europe, a five-year, $6 million grant to study the KLF2 transcription factor. Schwartz will oversee the North American researchers of the network, marking the fourth time a Yale professor has played such a role.
Two years ago, a postdoctoral researcher in the Schwartz Lab, Brian G. Coon, PhD, used the gene-editing tool CRISPR to perform a genome-wide screen in endothelial cells, the cells that line blood vessels. The friction generated by blood flow past these cells induces KLF2 expression, and Schwartz and Coon wanted to know which genes mediate this process. “What we got out of it was astounding,” says Schwartz. The screen produced a hit list of 500 possible genes. “The trouble is, to really exploit this amount of data, you need a team,” he says.
Schwartz began reaching out to other investigators. After talking to a colleague about possible experiments and funding, “we decided that Leducq would be a good way to do it,” he says. They forged a team from both sides of the Atlantic and took their plan to Leducq, which endorsed it.
Based in Paris, Fondation Leducq was founded by the late Jean and Sylviane Leducq in 1996 to fund cardiovascular and neurovascular research. In 2003, the organization established the Transatlantic Networks of Excellence program to foster collaborative research in these domains. According to its mission statement, the fight against vascular disease is a battle that “should be waged at the international level.” Including the five 2018 grants, the foundation has supported 62 of these networks.
During the early stages of this project, Schwartz and his network will develop tools to test the hit list’s genetic targets. The Schwartz Lab will receive $1.16 million of the grant to unravel the signaling network that allows blood flow to influence KLF2 expression. Other investigators will test these genes in vitro in endothelial cells as well as in vivo in mice. At the end of the grant period, Schwartz says, “we will have realistic drug targets.”
Schwartz projects confidence in his team’s ability to push vascular research forward. “I think it’s a problem that is ripe to be solved.” he says.