Molecular mechanisms underlying Arteriovenous Malformations associated with HHT

HHT 相关动静脉畸形的分子机制

基本信息

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
项目类别：
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

项目摘要

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.

项目概要遗传性出血性毛细血管扩张症 (HHT) 是一种影响男性的常染色体显性遗传病以及来自所有种族和族裔群体的女性，每 5000 人中就有 1 人患有 HHT。由动脉和静脉之间的不适当连接引起，称为动静脉畸形 (AVM)。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。尽管之前已发现，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的研究 HHT 的遗传原因与转化有关。生长因子-β (TGFβ) 信号通路，大约 85% 的患者表现出生长因子-β (TGFβ) 信号通路突变内皮糖蛋白 (Eng) 或激活素受体样激酶 1 (Acvrl1) 辅助受体大约 4% 存在缺陷。下游转录因子，Smad相关蛋白4（Smad4）尽管多年来主要是HHT研究。专注于 Eng 和 Acvrl1，我们的知识中仍然存在两个关键差距 - 对 HHT 脉管系统的细胞形态和生物学缺陷以及下游基因的鉴定我们创建了一种新型小鼠模型因此，AVM/HHT 在血管中专门对 Smad4 进行基因消融，可以有效地复制细胞使用我们的模型，我们已经开始对与 HHT 相关的生物缺陷进行详细的分子和细胞研究。体内 HHT 血管的表征，以及初始 RNA-seq 和 ChIP-seq 实验已确定 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) 和转录辅助因子 Zmiz1 该应用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 TGFβ 通路下游效应器有哪些？我们将讨论这些主题。通过测试我们的假设，即 Smad4 转录控制下游通路组件通过以下具体目标，在机械上负责 AVM 的形成： 1) 识别分子和导致 AVM 形成的细胞事件以及与 AVM/HHT 相关的 Smad4 下游效应器 2) 检查 Tek/Angiopoietin 信号传导在 AVM 的生成和解决中的作用；3) 检查该作用； Zmiz1 在 AVM 发病机制中的作用从这些研究中获得的结果将加深我们对 AVM 发病机制的理解。 AVM 发病机制的机制介质并发现旨在治疗该疾病的新药物靶点 HHT 的机制。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Zmiz1 is a novel regulator of lymphatic endothelial cell gene expression and function.

Zmiz1 是淋巴内皮细胞基因表达和功能的新型调节因子。

DOI：
发表时间：
2023-07-22
期刊：
影响因子：
0
作者：
Rajan, K C;Patel, Nehal R;Shenoy, Anoushka;Scallan, Joshua P;Chiang, Mark Y;Galazo, Maria J;Meadows, Stryder M
通讯作者：
Meadows, Stryder M

Angiopoietin-2 Inhibition Rescues Arteriovenous Malformation in a Smad4 Hereditary Hemorrhagic Telangiectasia Mouse Model.

抑制血管生成素 2 可挽救 Smad4 遗传性出血性毛细血管扩张小鼠模型中的动静脉畸形。

DOI：
发表时间：
2019
期刊：
影响因子：
37.8
作者：
Crist, Angela M;Zhou, Xingyan;Garai, Jone;Lee, Amanda R;Thoele, Janina;Ullmer, Christoph;Klein, Christian;Zabaleta, Jovanny;Meadows, Stryder M
通讯作者：
Meadows, Stryder M

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

内皮细胞极性和细胞外基质组成在发育和病理性血管生成过程中需要功能性 ATP6AP2。