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BMP and Notch crosstalk in cerebral arteriovenous malformations

脑动静脉畸形中的 BMP 和 Notch 串扰

基本信息

批准号：
9927680
负责人：
Yucheng Yao
金额：
$ 33.69万
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：
2012
资助国家：
美国
起止时间：
2012-06-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9927680
关键词：
Affect Arteriovenous malformation Biological Assay Blood Vessels Bone Morphogenetic Proteins Brain Brain hemorrhage Cell Differentiation process Cells Cerebral Arteriovenous Malformations Cerebrovascular system Cerebrum ChIP-seq Chemicals Child Chromatin DNA Binding Data Defect Development Diagnosis Disease Endothelial Cells Endothelium Genes Genetic Transcription Hereditary hemorrhagic telangiectasia Human In Vitro Lead Ligands Lung Maintenance Massive Parallel Sequencing Mediating Mediator of activation protein Modeling Mus Neurologic Nucleic Acid Regulatory Sequences Play Prevention strategy Public Health Regulation Regulator Genes Role Signal Transduction Signaling Protein Ski-interacting protein Technology Testing Therapeutic Tissues Translating Vascular Diseases Vascular Endothelial Growth Factors Work Youth activin receptor-like kinase 1 brain endothelial cell cerebrovascular chromatin immunoprecipitation high throughput screening in vivo inhibitor/antagonist insight jagged1 protein knock-down malformation matrix Gla protein notch protein prevent receptor recruit sex treatment strategy vascular bed

项目摘要

ABSTRACT Therapeutic advances in vascular disease may have far-reaching public benefits. Bone morphogenetic proteins (BMPs) and Notch signaling are emerging as essential regulators of the vasculature, and important in disorders such as arteriovenous malformations (AVMs). Our previous studies have demonstrated that excess BMP induces Notch signaling causing cerebral AVMs. In preliminary studies, we demonstrate a strong endothelial induction of Sox2 in human cerebral AVMs, and a dramatic improvement of cerebral AVMs after limiting Sox2 in ECs. We find that excess transcriptional activity of Sox2 disrupts cerebral EC differentiation to cause lumen disorder in AVMs. Sox2 is regulated by crosstalk of BMP and Notch signaling. In vitro, we show that BMP-induced Notch ligands Jagged 1 and 2 upregulate Sox2, and knockdown of Notch1 receptor diminishes Sox2 induction. In vivo, Jagged 1 and 2 and Notch1 are increased and directly targeted Sox2 in MGP-deficient cerebral ECs, in which a decrease of Jagged 1 or 2 reduces Sox2 expression. In contrast, we find no induction or significant changes of transcriptional effects of Sox2 in pulmonary AVMs, where instead the expression of VEGF is increased. Limiting endothelial Sox2 does not improve pulmonary AVMs. To induce Sox2, Notch requires ski-interacting protein (Skip), which is active in brain ECs but inactive in pulmonary ECs. Furthermore, we have created a high throughput-screening model and aim to identify chemical compounds that suppress Sox2 expression in brain ECs. We hypothesize that regulation of Sox2 and its transcriptional activity is important in the maintenance of EC differentiation and lumen formation in normal cerebral vasculature. Specific Aim 1 will determine how Sox2 is regulated by BMP and Notch signaling and affects the differentiation of brain endothelial cells. Specific Aim 2 will determine if Sox2 is induced to contribute to human cerebral AVMs. Specific Aim 3 will determine how regulation of Sox2 differs in cerebral versus pulmonary AVMs and identify the chemical compounds that suppress Sox2 expression. If successful, the obtained information may translate into strategies for using Sox2 inhibitors in the treatment of cerebral AVMs. The study may also provide significant insights of tissue-specific formation of AVMs, and lead to different treatment strategies for AVMs.

摘要