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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：
10518011
负责人：
Yucheng Yao
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：
2012
资助国家：
美国
起止时间：
2012-06-01 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10518011
关键词：
ACVRL1 gene Abnormal Endothelial Cell Affect Animal Model Arteriovenous malformation Back Blood Vessels Bone Morphogenetic Proteins Brain Brain hemorrhage Cell Differentiation process Cell model Cells Child Data Disease Endothelial Cells Endothelium Enhancers Enzymes Epigenetic Process Gene Proteins Genetic Genetic Transcription HDAC2 gene Hereditary hemorrhagic telangiectasia Histone Acetylation Histone Deacetylase Histone Deacetylase Inhibitor Histone H3 Histone H4 Homologous Gene Human Juvenile polyposis syndrome Lead LoxP-flanked allele Lysine Maintenance Maps Mesenchymal Micrococcal Nuclease Modeling Mus Neurologic Deficit Physiologic arteriovenous anastomosis Population Prevention strategy Proteins Public Health Resolution Role Shunt Device Signal Transduction Specificity Specimen System Targeted Toxins Technology Testing Therapeutic Toxin Work base brain arteriovenous malformations brain endothelial cell cerebrovascular histone deacetylase 2 histone modification improved inhibitor insight malformation matrix Gla protein mouse model notch protein novel therapeutic intervention prevent repaired single-cell RNA sequencing

项目摘要

SUMMARY Cerebral arteriovenous malformations (AVMs) are the most common vascular malformations and the leading cause of hemorrhagic strokes. Past studies have demonstrated an important role of endothelial cells (ECs) in cerebral AVMs, and shown that the maintenance of endothelial integrity by bone morphogenetic protein (BMP) and Notch signaling is critical for cerebral vascular formation. However, it is unclear how disturbed crosstalk between BMP and Notch signaling affects EC differentiation at transcriptional regulatory level causing cerebral AVMs. In this proposal, we aim to unearth that the crosstalk between BMP and Notch signaling induces histone deacetylase 2 (HDAC2) to shift the transcriptional landscape of ECs toward ill-fated differentiation causing cerebral AVMs. We will also define if HDAC2 inhibition prevents this ill-fated cell shift and improves cerebral AVMs. In preliminary study, using a new mouse model, we find a striking shift of ECs to mesenchymal-like cells in cerebral AVMs and show that these mesenchymal-like cells cause arteriovenous shunts. Utilizing single-cell RNA sequencing and connectivity Map, we identify HDAC inhibition to prevent ECs from mesenchymal cell differentiation and significantly reduce cerebral AVMs. In human and mouse cerebral AVMs, we find a specific HDAC2 induction. We show that HDAC2 induction alters specific histone modifications, which are responsible for the shift of ECs to mesenchymal cell differentiation. Endothelial-specific deletion of HDAC2 prevents this ill- fated cell shift and reduces cerebral AVMs. Similar results of dysregulated HDAC2 with its downstream effects are also found in cerebral AVMs of hereditary hemorrhagic telangiectasia type 1 (HHT1) and type 2 (HHT2), but not in juvenile polyposis/HHT. Furthermore, we find that HDAC2 is specifically induced in cerebral AVMs by excess BMP through delta-like protein 3 (Dll3) and Notch1 signaling. We uncover that lack of matrix Gla protein (MGP) allows BMP-8b to elevate staphylococcal nuclease domain-containing protein 1 (SND1), which is required for Notch signaling to induce HDAC2 in cerebral AVMs. We hypothesize that HDAC2 induction, downstream of excess BMP and Notch signaling, alters specific histone modifications to shift ECs toward ill-fated differentiation causing cerebral AVMs. In specific Aim 1, we will determine how HDAC2 is dysregulated by the crosstalk between BMP and Notch signaling and shifts endothelial differentiation in cerebral AVMs. In specific Aim 2, we will determine the contribution of HDAC2 induction to human cerebral AVMs. In specific Aim 3, we will determine if limiting HDAC2 improves cerebral AVMs. If successful, the obtained information will provide new insight into the mechanism of AVMs, and HDAC2 inhibition may emerge as a novel therapeutic approach for cerebral AVMs.

总结