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

研究由 BMP、Notch、介导的潜在 MGP 负反馈回路

• 批准号: 8653273
• 负责人: Allan R Albig
• 金额: $ 22.37万
• 依托单位: BOISE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8653273
• 关键词: Applications Grants; Arteries; Arteriosclerosis; Atherosclerosis; Biology; Biomedical Research; Blood Vessels; Bone Morphogenetic Proteins; Cardiovascular Diseases; Centers of Research Excellence; Data; Developed Countries; Disease; Elasticity; Extracellular Matrix; Extracellular Matrix Proteins; Feedback; Funding; Future; Genetic Polymorphism; Genetic Transcription; Goals; Health; Homeostasis; Human; Investigation; Knockout Mice; Lead; Ligands; Link; Mediating; Mentors; Molecular; Process; Publishing; Research Personnel; Risk; Role; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Societies; Testing; Tissues; Transcriptional Activation; Vascular calcification; Work; angiogenesis; base; calcification; improved; literature survey; matrix Gla protein; mineralization; notch protein; novel; prevent; protein expression; protein function; research study

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.

细胞外基质矿化异常与西方社会一些最普遍和致命的疾病有关，包括动脉粥样硬化和动脉硬化。了解异常基质矿化进行的分子机制是更好地治疗这些疾病的重要的第一步。基质 Gla 蛋白 (MGP) 是一种细胞外基质蛋白，是组织矿化的强大抑制剂。 MGP 基因敲除小鼠会出现严重的主动脉钙化，而人类的 MGP 多态性与发生动脉钙化的风险增加有关。尽管 MPG 在预防血管矿化方面发挥着重要作用，但控制 MGP 表达和 MGP 功能的分子机制仅部分了解。我们的初步数据和已发表的结果表明，MGP 控制 Notch 信号传导，这是一种与骨形态发生蛋白协同控制血管生物学的重要信号传导途径。这一观察结果打开了一扇门，可能会让我们更好地了解 MGP 在血管健康中的作用。在本提案中，我们将研究两个具体目标。首先，我们相信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方面发挥着重要作用。其次，我们将继续研究 MGP 控制 Notch 信号传导的分子机制，我们假设这是 MGP 功能的一个方面，对于抑制动脉基质矿化非常重要。完成这些研究后，我们将对 MGP 在动脉健康中的作用有新的认识。作为 COBRE 基质生物学的初级研究员，我将与我的科学导师合作，完成科学目标并为未来的 R01 资金制定拨款提案。