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，异常瓣膜力学和炎症和慢性肾功能不全的常见结果。一旦思考良性，钙化血管病的有害临床后果现已变得明显。它是导致CVA，ML和PVD的病理生理学的关键组成部分，其截肢和心血管死亡率受到钙化血管病的解剖和程度所赋予的范围。治愈或实质性逆转大血管钙化（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。成骨和炎症基因调节程序在MVC中被激活，涉及外在，内侧，内膜和瓣膜组织 - 通过控制骨生理的机制重叠。我们已经表明，一个促肌生成的程序 - “馈送” BMP2-MSX2-WNT信号级联 - 由糖尿病和血脂异常激活。相比之下，PTH/PTHRP受体激动剂（例如Teriparatide）抑制血管肌纤维细胞钙化和主动脉MSX2-WNT基因表达。现在，我们研究了MVC中肌纤维细胞MSX2-WNT信号的作用和调节。在AIM 1中，我们使用ldlr - / - 。topgal+记者小鼠（在Wnt响应性TCF/LEF元件中控制的LACZ Transgene）将主动脉Wnt信号传导的空间激活与饮食诱导的MSX2-WNT表达和从饮食中的表达相关联，并从Advenitial sendedial repanditors招募了OsteTitial odsepoprogentors。，内侧和瓣膜肌纤维细胞。我们还测试了我们在CMV-MSX2转基因小鼠中观察到的增强主动脉钙化和WNT表达是否激活了主动脉LACZ的表达。原发性主动脉肌纤维细胞的共培养研究将测试MSX2激活的旁分泌列表信号传导是否受到PTH的抑制（1-34）。在使用topgal小鼠的AIM 2中，我们测试PTH（1-34）是否抑制体内规范Wnt信号传导。在AIM 3中，我们绘制了MSX2启动子蛋白-DNA相互作用，这些相互作用将转录抑制传达到肌纤维细胞中的PTH（1-34），强调介导BMP2和WNT激活的元素。