Investigation of a potential MGP negative feedback loop mediated by BMP, Notch,

Abnormal extracellular matrix mineralization is associated with some ofthe most prevalent and deadly diseases of western societies including atherosclerosis and arteriosclerosis. Understanding the molecular mechanisms by which abnormal matrix mineralization proceeds is an important first step toward better treatment for these diseases. Matrix Gla Protein (MGP) is an extracellular matrix protein that is a powerful suppressor of tissue mineralization. MGP knockout mice develop extreme aortic calcification, and MGP polymorphisms in humans are associated with increased risk of developing arterial calcification. Despite the important role of MPG in preventing vascular mineralization, the molecular mechanisms by which MGP expression is controlled and by which MGP functions are only partly understood. Our preliminary data and published results have shown that MGP controls Notch signaling, an important signaling pathway that synergizes with Bone Morphogenetic Proteins to control vascular biology. This observation has opened a door that may lead us to a better understanding of the role of MGP in vascular health. In this proposal, we will examine two specific aims. First, we believe we have identified a previously unknown negative feedback mechanism that we hypothesize serves an important role to control MGP expression and vascular extracellular matrix calcification. Second, we will continue to examine the molecular mechanism(s) by which MGP controls Notch signaling, an aspect of MGP function that we hypothesize is important for suppressing arterial matrix mineralization. Upon completion of these studies, we will arrive at a new understanding ofthe role of MGP in arterial health. As a Junior Investigator in the COBRE in Matrix Biology, I will work with my scientific mentor to complete the scientific aims and to develop a grant proposal for future R01 funding.