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Molecular Mechanisms of MGP; Role in AVMs

MGP的分子机制；

基本信息

批准号：
9915958
负责人：
Kristina I Bostrom
金额：
$ 39万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-24 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9915958
关键词：
ACVRL1 gene Address Antibodies Arteries Arteriovenous malformation BMP4 Behavior Binding Blood Blood Vessels Blood capillaries Bone Morphogenetic Proteins Caliber Cardiac Output Cell Differentiation process Cells Clinical Crossbreeding Data Development Differentiation Antigens Differentiation Inhibitor Disease Endothelial Cells Endothelium Expression Profiling Feedback Gene Deletion Gene Expression Gene Proteins Generations Goals Growth Heart Heart Diseases Heart failure Hemorrhage Hereditary hemorrhagic telangiectasia Immunoblotting Impairment In Vitro Knock-in Mouse Lead Ligands Link Liver Location Lung Mediating Modeling Molecular Morphogenesis Mouse Protein Mus Mutation Organ Participant Pattern Penetrance Periodicity Phenotype Play Point Mutation Proline Protein Deficiency Protein Inhibition Proteins Public Health Regulation Retina Role Shapes Signal Transduction Stroke System Techniques Thinness Vascular System Veins Wild Type Mouse Work activin receptor-like kinase 1 bone morphogenetic protein 9 density design in vivo inhibitor/antagonist malformation matrix Gla protein mouse model notch protein novel preference protein expression protein function receptor response small hairpin RNA targeted treatment therapy design time use tissue regeneration treatment strategy

项目摘要

PROJECT SUMMARY: The vascular system consists of elaborate networks that develop in combination with close regulation of endothelial cells (ECs). An understanding of such regulation is essential for the development of new treatment strategies aimed at vascular malformations, such as arteriovenous malformations (AVMs) and hereditary hemorrhagic telangiectasia (HHT), caused by mutations in activin receptor-like kinase 1 (ALK1). We previously showed that gene deletion in mice of matrix Gla protein (MGP), an inhibitor of bone morphogenetic proteins (BMPs), causes AVMs in multiple organs similar to HHT. We showed that BMP9/ALK1 signaling induces MGP expression in ECs, where MGP plays an important role in differentiation. BMP9/ALK1 signaling also induces Crossveinless-2 (CV2) with a different induction delay, thereby creating two negative feedback loops. Together, MGP and CV2 regulate BMP9 signaling by a previously unknown mechanism. In cultured ECs, we found oscillations of MGP and CV2 expression that temporally coordinated transition to EC stalk cell phenotype in ECs. This also caused markers of stalk cells to oscillate, whereas tip cell markers were suppressed. Deletion of Mgp abolished the oscillatory behavior. In vivo, MGP and CV2 were seen as “shaping waves” or stripes in the growing retina, and lack of MGP perturbed the vascular networks. Our hypothesis is that MGP and CV2 are regulators of BMP9 signaling and vascular morphogenesis through generation of oscillations or waves of expression. In Aim 1, we will characterize how MGP and CV2 orchestrate EC differentiation in response to BMP9 using oscillations of gene expression. We will relate BMP9-induced stalk cell phenotype to the oscillations, and explore expression profiles of ECs capable of this behavior. We will disrupt the system by deleting the Mgp gene in vitro using established techniques of shRNA, and determine the effect on the waves of inhibitors and stalk cell markers. We will also investigate whether waves of MGP and CV2 can be detected in normal vasculature, with focus on the retina. In Aim 2, we will obtain key information about the role of MGP in retinal vascular networks and AVMs by deleting Mgp, impairing MGP protein function, and modulating the cellular origin. We will modulate potential targets for AVM treatments using the Mgp-/- mice as an AVM model. We will start with modulation of CV2 and use approaches that include crossbreeding with genetically altered mice and transmammary immunoblocking, and subsequently screen other factors in the BMP9 response. Our studies will help identify targets in the BMP9 response system that might be used in designing treatments for AVMs.

项目总结: