MSX2-Wnt Signaling in Cardiovascular Calcification

心血管钙化中的 MSX2-Wnt 信号转导

基本信息

批准号：
7258917
负责人：
DWIGHT A. TOWLER
金额：
$ 36.03万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-09-30 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7258917
关键词：
Actins Age Aging Agonist Amputation Anatomy Aortic Valve Stenosis Appendix Arteries Arts BMP2 gene Benign Biological Assay Blood Vessels Calcified Calcium Cardiovascular system Cells Characteristics Chronic Chronic Kidney Insufficiency Classification Clinical Coculture Techniques Complex DNA-Protein Interaction Data Deposition Development Diabetes Mellitus Diet Disease Dyslipidemias Elements Endocrine Fibroblasts Fracture Functional disorder Galactosidase Gene Chips Gene Expression Genetic Transcription Growth Health Healthcare Homeodomain Proteins Hormones Human Hypertension Immunofluorescence Immunologic In Situ In Situ Hybridization In Vitro Inflammation Inflammatory Injury Kidney Laboratories LacZ Genes Lead Ligands Lipids Lipoproteins Lower Extremity Maps Mechanics Medial Mediating Metabolic Modeling Molecular Mus Myofibroblast Nuclear Osteoblasts Paracrine Communication Parathyroid Hormone Receptor Patients Physiology Postmenopause Process Production Productivity Proliferating Proteins Recruitment Activity Regulation Regulator Genes Regulatory Element Reporter Research Personnel Risk Role Signal Transduction Skeletal system Smooth Muscle Myocytes Staining method Stains Stem cells Stroke Study models Teriparatide Testing Thinking Time Tissues Transgenes Transgenic Mice Transgenic Model Up-Regulation Vascular Diseases Vascular calcification Woman Work aortic arch beta catenin bone calcification diabetic feeding hypercholesterolemia improved in vitro Model in vivo inhibitor/antagonist macrovascular disease mineralization morphogens mortality novel strategies paracrine parathyroid hormone (1-34)prevent progenitor programs promoter response seal

项目摘要

DESCRIPTION (provided by applicant): Cardiovascular calcification is a common consequence of aging, diabetes, hypercholesterolemia, hypertension, abnormal valve mechanics & inflammation, & chronic renal insufficiency. Once thought benign, the deleterious clinical consequences of calcific vasculopathy are now becoming clear; it is a key component of pathophysiology leading to CVA, Ml, and PVD -- with amputation and cardiovascular mortality portended by the anatomy and extent of calcific vasculopathy. The ability to cure or substantially reverse macrovascular calcification (MVC) represents an unmet clinical need. A better understanding of MVC initiation and progression is required. Osteogenic & inflammatory gene regulatory programs are activated in MVC-- variably involving adventitial, medial, intimal, and valvular tissues -- via mechanisms overlapping those that control bone physiology. We've shown that a pro-osteogenic program -- a "feed-forward" BMP2-Msx2-Wnt signaling cascade -- is activated in aortic myofibroblasts by diabetes and dyslipidemia. By contrast, PTH/PTHrP receptor agonists (e.g., teriparatide) suppress vascular myofibroblast calcification and aortic Msx2-Wnt gene expression. We now study the role and regulation of myofibroblast Msx2-Wnt signaling in MVC. In Aim 1, we use LDLR-/-.TOPGAL+ reporter mice (LacZ transgene under control of Wnt-responsive TCF/LEF element) to relate spatial activation of aortic Wnt signaling to diet-induced Msx2-Wnt expression and recruitment of osteoprogenitors from adventitial, medial, & valvular myofibroblasts. We also test if the enhanced aortic calcification and Wnt expression we observe in CMV-Msx2 transgenic mice activates aortic LacZ expression. Co-culture studies of primary aortic myofibroblasts will test if Msx2--activated paracrine Writ signaling is inhibited by PTH (1-34). In Aim 2, using TOPGAL mice, we test if PTH(1-34) inhibits canonical Wnt signaling in vivo. In Aim 3, we map Msx2 promoter protein-DNA interactions that convey transcriptional suppression to PTH(1-34) in myofibroblasts, emphasizing elements that mediate BMP2 and Wnt activation.

描述（由申请人提供）：心血管钙化是衰老、糖尿病、高胆固醇血症、高血压、瓣膜力学异常和炎症以及慢性肾功能不全的常见后果。钙化性血管病曾经被认为是良性的，但其有害的临床后果现在变得越来越明显。它是导致 CVA、MI 和 PVD 的病理生理学的关键组成部分——钙化性血管病的解剖结构和程度预示着截肢和心血管死亡率。治愈或基本上逆转大血管钙化（MVC）的能力代表了未满足的临床需求。需要更好地了解 MVC 的启动和进展。成骨和炎症基因调控程序在 MVC 中被激活——不同程度地涉及外膜、内侧、内膜和瓣膜组织——通过与控制骨生理学的机制重叠的机制。我们已经证明，糖尿病和血脂异常会激活主动脉肌成纤维细胞中的促成骨程序（“前馈”BMP2-Msx2-Wnt 信号级联）。相比之下，PTH/PTHrP 受体激动剂（例如特立帕肽）抑制血管肌成纤维细胞钙化和主动脉 Msx2-Wnt 基因表达。我们现在研究肌成纤维细胞 Msx2-Wnt 信号在 MVC 中的作用和调节。在目标 1 中，我们使用 LDLR-/-.TOPGAL+ 报告小鼠（Wnt 响应 TCF/LEF 元件控制下的 LacZ 转基因）将主动脉 Wnt 信号传导的空间激活与饮食诱导的 Msx2-Wnt 表达以及从外膜中招募骨祖细胞联系起来。、内侧和瓣膜肌成纤维细胞。我们还测试了在 CMV-Msx2 转基因小鼠中观察到的主动脉钙化增强和 Wnt 表达是否激活主动脉 LacZ 表达。原代主动脉肌成纤维细胞的共培养研究将测试 Msx2 激活的旁分泌 Writ 信号是否被 PTH 抑制 (1-34)。在目标 2 中，我们使用 TOPGAL 小鼠测试 PTH(1-34) 是否在体内抑制经典 Wnt 信号传导。在目标 3 中，我们绘制了在肌成纤维细胞中向 PTH(1-34) 传递转录抑制的 Msx2 启动子蛋白-DNA 相互作用，强调了介导 BMP2 和 Wnt 激活的元件。