Grant: Project Grant

Keeping our blood vessels healthy is essential for preventing heart and blood pressure problems such as high blood pressure and stiff arteries. Matrix Gla Protein (MGP) is a key protective molecule that prevents the dangerous buildup of calcium phosphate minerals in blood vessels. This buildup, known as vascular calcification, can be life-threatening, especially when it occurs alongside heart disease. For MGP to function properly, specific regions of the protein called serine residues must undergo a process known as phosphorylation, in which a small chemical group is added. Our research focuses on understanding how MGP blocks calcium phosphate mineral formation and how changes, or mutations, in the MGP gene can damage blood vessels. Laboratory studies from our group indicate that another protein, FAM20C, is responsible for phosphorylating MGP. This modification helps MGP bind to and inhibit mineral deposits. We have also identified a specific MGP mutation, called Cys19Phe, which prevents the protein from being released from the cell. As a result of this mutation, stress builds up inside the cell and alters the behavior of blood vessel muscle cells. Unlike the complete absence of MGP, which causes extensive mineral deposits, this mutation leads to thickening of the artery walls and changes in the surrounding matrix. These alterations impair normal blood vessel function and are associated with rare vascular disorders in patients, including moyamoya disease. In this project, we will investigate in detail how MGP is phosphorylated, the role of FAM20C in this process, and how the Cys19Phe mutation affects blood vessel health. By using specialized genetically modified mouse models and targeted drug treatments, we aim to identify new strategies to prevent calcium phosphate mineral buildup and harmful vascular remodeling, ultimately helping to preserve cardiovascular health throughout life.