Molecular mechanisms underlying Arteriovenous Malformations associated with HHT

HHT 相关动静脉畸形的分子机制

• 批准号: 10455509
• 负责人: Stryder Medoah Meadows
• 金额: $ 38万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-18 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10455509
• 关键词: Ablation; Address; Affect; Anemia; Aneurysm; Angiopoietin-2; Angiopoietins; Animal Model; Arteries; Arteriovenous malformation; Automobile Driving; Biological; Blood Vessels; Blood flow; Cells; Cellular Morphology; Cessation of life; ChIP-seq; Chronic; Data; Defect; Development; Developmental Biology; Disease; Dominant Genetic Conditions; Drug Targeting; Endoglin; Endothelium; Epistaxis; Ethnic group; Event; Female; Gene Expression; Generations; Genes; Genetic; Genetic Diseases; Genetic Transcription; Genomics; Hereditary hemorrhagic telangiectasia; Knowledge; Link; Mediator of activation protein; Methods; Modeling; Molecular; Mutation; Operative Surgical Procedures; Organ; Pathogenesis; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Phenotype; Proteins; Race; Research; Resolution; Risk; Role; Rupture; Signal Pathway; Signal Transduction; Signaling Protein; Stroke; Telangiectasis; Testing; Transcriptional Regulation; Transforming Growth Factors; Vascular remodeling; Veins; Work; activin receptor-like kinase 1; antagonist; base; design; effective therapy; experimental study; in vivo; innovation; loss of function mutation; male; mouse model; mutant; new therapeutic target; novel; receptor; success; targeted treatment; transcription factor; transcriptome sequencing

PROJECT SUMMARY Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant genetic disease that affects males and females from all racial and ethnic groups, and is found in ~1 in every 5000 people. HHT is characterized by inappropriate connections between arteries and veins, called arteriovenous malformations (AVMs). These fragile connections can bleed and rupture leading to anemia, aneurysms, stroke and even death. Remarkably, there are currently no drugs for effective treatment of AVMs in HHT patients, despite the previous identification of the defective signaling pathway associated with HHT. Genetic causes of HHT are linked to the Transforming Growth Factor-β (TGFβ) signaling pathway, with approximately 85% of patients showing mutations in the Endoglin (Eng) or Activin receptor-like kinase 1 (Acvrl1) co-receptors. About 4% have defects in the downstream transcription factor, Smad-related protein 4 (Smad4). Despite many years of HHT research mainly focused on Eng and Acvrl1, two crucial gaps in our knowledge remain - a comprehensive understanding of the cell morphological and biological defects of the HHT vasculature, and identification of the downstream genes that are mechanistically responsible for the vascular defects. We have created a novel mouse model of AVM/HHT whereby genetic ablation of Smad4 specifically in blood vessels effectively replicates the cell biological defects associated with HHT. Using our model we have begun a detailed molecular and cellular characterization of HHT vessels in vivo, and initial RNA-seq and ChIP-seq experiments have identified potential novel regulators of AVM/HHT, including the vascular signaling proteins Tek and Angiopoietin 2 (Ang2), and the transcriptional co-factor Zmiz1. The central objective of this application is to answer two fundamental questions: What are the molecular and cellular mechanisms driving AVM/HHT pathogenesis and what are the downstream effectors of the TGFβ pathway that promote AVM/HHT? We will address these topics by testing our hypothesis that Smad4 transcriptionally controls downstream pathway components that are mechanistically responsible for AVM formation, via the following specific aims: 1) Identify the molecular and cellular events causing AVM formation and the Smad4 downstream effectors associated with AVM/HHT; 2) Examine the role of Tek/Angiopoietin signaling in generation and resolution of AVMs; and 3) Examine the role of Zmiz1 in AVM pathogenesis. Results obtained from these studies will advance our understanding of the mechanistic mediators of AVM pathogenesis and uncover new drug targets designed to treat the disease mechanisms of HHT.

项目摘要 遗传性出血性毛细血管扩张症（HHT）是一种常染色体显性遗传疾病，好发于男性 所有种族和民族的女性，每5000人中就有1人。HHT的特点是 由于动脉和静脉之间的不适当连接，称为动静脉畸形（AVM）。这些 脆弱的连接可能会出血和破裂，导致贫血、动脉瘤、中风甚至死亡。值得注意的是， 尽管先前已确定，但目前尚无有效治疗HHT患者AVM的药物 与HHT相关的缺陷信号通路。HHT的遗传原因与转化有关 生长因子-β（TGF β）信号传导通路，约85%的患者显示TGF β基因突变。 内皮糖蛋白（Eng）或激活素受体样激酶1（Acvrl1）共受体。大约4%的人有缺陷 下游转录因子Smad相关蛋白4（Smad4）。尽管多年来HHT的研究主要是 虽然我们的知识集中在Eng和Acvrl 1上，但仍然存在两个关键的差距--对 HHT血管系统的细胞形态学和生物学缺陷，以及下游基因的鉴定 它们在机械上导致了血管缺陷。我们创造了一种新的小鼠模型， AVM/HHT，其中在血管中特异性地基因消融Smad4有效地复制细胞 与HHT相关的生物学缺陷。使用我们的模型，我们已经开始了详细的分子和细胞 HHT血管在体内的表征，以及最初的RNA-seq和ChIP-seq实验已经确定了 AVM/HHT的潜在新型调节剂，包括血管信号蛋白Tek和血管生成素2 （Ang2）和转录辅因子Zmiz1。本应用程序的中心目标是回答两个问题 基本问题：驱动AVM/HHT发病机制的分子和细胞机制是什么， 促进AVM/HHT的TGF β通路的下游效应物是什么？我们将讨论这些主题 通过测试我们的假设，即Smad4转录控制下游通路成分， 通过以下具体目标，对AVM形成的机制负责：1）识别分子和 导致AVM形成的细胞事件和与AVM/HHT相关的Smad4下游效应物; 2） 检查Tek/血管生成素信号在AVM生成和消退中的作用; 3）检查 Zmiz1在AVM发病机制中的作用。从这些研究中获得的结果将促进我们对 AVM发病机制的机制介质，并发现设计用于治疗疾病的新药物靶点 HHT的机制。

项目成果

Endothelial cell polarity and extracellular matrix composition require functional ATP6AP2 during developmental and pathological angiogenesis.

• DOI: 10.1172/jci.insight.154379
• 发表时间: 2022-10-10
• 期刊: JCI INSIGHT
• 影响因子: 8
• 作者: Patel, Nehal R.;Rajan, K. C.;Blanks, Avery;Li, Yisu;Prieto, Minolfa C.;Meadows, Stryder M.
• 通讯作者: Meadows, Stryder M.