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.

总结 脑动静脉畸形（AVM）是最常见的血管畸形， 出血性中风的原因过去的研究已经证明了内皮细胞（EC）在血管生成中的重要作用。 脑动静脉畸形，并表明，维持内皮完整性的骨形态发生蛋白（BMP）， Notch信号对脑血管形成至关重要。然而，目前还不清楚干扰串扰 BMP和Notch信号之间的相互作用在转录调节水平上影响EC分化， 反车辆地雷。在这个提议中，我们的目标是发现BMP和Notch信号之间的串扰诱导组蛋白 去乙酰化酶2（HDAC 2）将EC的转录景观向命运不佳的分化转变， 脑动静脉畸形我们还将确定HDAC 2抑制是否能阻止这种命运多舛的细胞转移，并改善大脑 反车辆地雷。在初步的研究中，我们使用一种新的小鼠模型，发现EC向间充质样细胞的显著转变 在脑动静脉畸形，并显示这些间充质样细胞引起动静脉分流。利用单细胞 通过RNA测序和连接图，我们鉴定了HDAC抑制以防止间充质细胞的EC 分化和显着减少脑AVM。在人类和小鼠脑AVM中，我们发现了一种特异性的 HDAC 2诱导。我们发现HDAC 2诱导改变了特定的组蛋白修饰，这是导致 EC向间充质细胞分化的转变。HDAC 2的内皮特异性缺失可防止这种疾病- 减少脑动静脉畸形HDAC 2失调及其下游效应的类似结果 也见于遗传性出血性毛细血管扩张症1型（HHT 1）和2型（HHT 2）的脑AVM，但 而在青少年息肉病/HHT中没有。此外，我们发现HDAC 2在脑AVM中被特异性诱导， 过量的BMP通过δ样蛋白3（Dll 3）和Notch 1信号传导。我们发现缺乏基质Gla蛋白 (MGP)允许BMP-8 b升高所需的葡萄球菌含核酸酶结构域蛋白1（SND 1） 用于Notch信号传导以诱导脑AVM中的HDAC 2。我们假设HDAC 2诱导，下游的 过量的BMP和Notch信号传导，改变特定的组蛋白修饰，使EC转向注定失败的分化 导致脑动静脉畸形在具体的目标1中，我们将确定HDAC 2如何被串扰失调 BMP和Notch信号之间的联系，并改变脑AVM中的内皮分化。在具体目标2中，我们 将确定HDAC 2诱导对人脑AVM的贡献。在具体目标3中，我们将确定 如果限制HDAC 2可以改善脑AVM。如果成功，所获得的信息将提供新的见解， HDAC 2抑制剂可能成为脑AVM的一种新的治疗方法。