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

细胞外基质矿化异常与动脉粥样硬化和动脉硬化等西方社会最常见和最致命的疾病有关。了解异常基质矿化发生的分子机制是更好地治疗这些疾病的重要的第一步。基质玻璃蛋白（MGP）是一种细胞外基质蛋白，是一个强大的组织矿化抑制。MGP基因敲除小鼠会发生严重的主动脉钙化，而人类的MGP多态性与动脉钙化的风险增加有关。尽管MPG在防止血管矿化中起着重要作用，但控制MGP表达的分子机制和MGP的功能仅部分被了解。我们的初步数据和已发表的结果表明，MGP控制Notch信号通路，这是一个与骨形态发生蛋白协同控制血管生物学的重要信号通路。这一观察结果为我们更好地理解MGP在血管健康中的作用打开了一扇门。在本建议中，我们将探讨两个具体目标。首先，我们认为我们已经确定了一种以前未知的负反馈机制，我们假设该机制在控制MGP表达和血管细胞外基质钙化中起重要作用。其次，我们将继续研究MGP控制Notch信号的分子机制，我们假设MGP功能的一个方面对抑制动脉基质矿化很重要。在完成这些研究后，我们将对MGP在动脉健康中的作用有一个新的认识。作为矩阵生物学COBRE的初级研究员，我将与我的科学导师一起完成科学目标，并为未来的R01基金制定拨款提案。

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.