Development and disease of the arterial valves

One in every hundred babies is born with a bicuspid aortic valve—a heart valve that has two flaps instead of three—and many will face progressive narrowing, calcification, and dangerous bulging of the aorta as they age. The problem is that large genomic studies have turned up hundreds of gene variants of unknown significance linked to this condition, but no one can tell which ones actually cause disease. Without reliable lab tests to sort harmless variants from dangerous ones, doctors cannot predict who will develop severe valve disease or warn family members of their risk. The root cause is a gap in fundamental knowledge: scientists do not yet understand exactly how a normal three-flap aortic valve forms in the embryo, or which developmental steps fail to produce the two-flap version. This programme grant will first map the cellular and molecular mechanisms that remodel the developing arterial valve into its mature shape. The team will then pinpoint how those mechanisms break down in bicuspid valve disease. Finally, they will build cell-based assays that can test whether a specific gene variant actually disrupts valve formation. If successful, these assays will let clinicians interpret data from the 100,000 Genomes Project and other studies, turning ambiguous genetic results into actionable predictions about disease progression and inherited risk.