BMP and Notch crosstalk in cerebral arteriovenous malformations

脑动静脉畸形中的 BMP 和 Notch 串扰

• 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
• 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

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.

概括 大脑动脉畸形（AVM）是最常见的血管畸形，而领先 出血性中风的原因。过去的研究表明，内皮细胞（EC）在 脑AVM，并表明骨形态发生蛋白（BMP）维持内皮完整性 Notch信号对于脑血管形成至关重要。但是，目前尚不清楚如何打扰串扰 BMP和Notch信号之间会影响转录调节水平的EC分化，导致脑 AVM。在此提案中，我们的目标是发掘出BMP和Notch信号之间的串扰会引起组蛋白 脱乙酰基酶2（HDAC2）将EC的转录景观转移到命运不良的分化中 大脑AVM。我们还将定义HDAC2抑制是否阻止这种命运不佳的细胞移位并改善脑 AVM。在初步研究中，使用新的小鼠模型，我们发现EC向间充质样细胞的显着转移 在脑AVM中，表明这些间充质样细胞引起动静脉分流。利用单细胞 RNA测序和连接图，我们确定HDAC抑制以防止ECS从间质细胞中 分化并显着减少脑AVM。在人类和小鼠脑AVM中，我们找到了一个特定的 HDAC2诱导。我们表明HDAC2诱导改变了特定的组蛋白修饰，这是负责的 为了将EC转移到间充质细胞分化。 HDAC2的内皮特异性缺失可防止这种情况 命运的细胞移位并减少大脑AVM。与其下游效应的失调HDAC2的相似结果相似 也可以在遗传性出血性毛细血管扩张1（HHT1）和2型（HHT2）的脑AVM中发现 不在少年息肉时间/HHT中。此外，我们发现HDAC2是由大脑AVM专门诱导的 通过Delta样蛋白3（DLL3）和Notch1信号传导过量的BMP。我们发现缺乏基质GLA蛋白 （MGP）允许BMP-8B提升含葡萄球菌核酸酶结构域1（SND1），这是必需的 用于缺口信号传导诱导脑AVM中的HDAC2。我们假设HDAC2诱导，下游 多余的BMP和Notch信号传导，改变了特定的组蛋白修饰以将EC转移到命运不良的分化 引起大脑AVM。在特定目标1中，我们将确定HDAC2如何被串扰失调 在BMP和Notch信号传导之间以及脑AVM中的内皮分化。在特定的目标2中，我们 将确定HDAC2诱导对人脑AVM的贡献。在特定目标3中，我们将确定 如果限制HDAC2会改善大脑AVM。如果成功，获得的信息将为您提供新的见解 AVM和HDAC2抑制的机制可能会成为脑AVM的一种新型治疗方法。