Angiopoietin-2 Signaling Targeted Therapeutics for Arteriovenous Malformations

血管生成素 2 信号传导靶向治疗动静脉畸形

• 批准号: 10420883
• 负责人: PHILIPPE MARAMBAUD
• 金额: $ 70.24万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10420883
• 关键词: Address; Affect; Anemia; Aneurysm; Angiogenic Factor; Angiopoietin-2; Angiopoietins; Animal Model; Arteries; Arteriovenous malformation; Blood; Blood Vessels; Brain; CXCR4 gene; Cell model; Cessation of life; Complex; Data; Defect; Development; Disease; Endoglin; Endothelial Cells; Exhibits; FDA approved; FOXO1A gene; FRAP1 gene; Gene Deletion; Genetic; Genetic Diseases; Genetic Transcription; Hemorrhage; Hereditary hemorrhagic telangiectasia; Intervention; Laboratories; Lead; Ligands; Link; Liver; Lung; Mediating; Metabolic; Methods; Modeling; Molecular; Mus; Operative Surgical Procedures; Organ; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Pharmacology; Phenotype; Physiological; Positioning Attribute; Process; Proteins; Proteomics; Retinal Diseases; Risk; Rupture; Signal Pathway; Signal Repression; Signal Transduction; Stroke; TIE-2 Receptor; Telangiectasis; Testing; Transcriptional Activation; Transcriptional Regulation; Transforming Growth Factor beta; Transforming Growth Factors; Veins; Work; activin receptor-like kinase 1; base; causal variant; chemokine; design; druggable target; effective therapy; imaging modality; inhibitor; loss of function; loss of function mutation; mouse model; new therapeutic target; novel; overexpression; prevent; receptor; targeted treatment; therapeutic target; transcription factor; transcriptomics; vascular bed

PROJECT SUMMARY Hereditary Hemorrhagic Telangiectasia (HHT) is a vascular genetic disorder characterized by enlarged, leaky small vessels (telangiectasias) and inappropriate, fragile connections between arteries and veins called arteriovenous malformations (AVMs). HHT patients develop AVMs in a specific subset of major organs, which can rupture causing severe hemorrhage and anemia, as well as aneurysms, stroke and even death. Causes of HHT are linked to the Transforming Growth Factor-beta (TGF-beta) signaling pathway, with over 90% of patients exhibiting heterozygous loss-of-function mutations in the Activin receptor-like kinase 1 (Acvrl1/Alk1) or Endoglin (Eng) co-receptors, or the downstream transcription factor, Smad-related protein 4 (Smad4). Despite knowing the causative mutations, a significant gap remains in our understanding of the immediate TGF-beta downstream signaling components responsible for HHT pathologies. Furthermore, no cure is currently available for HHT. We have found that directly downstream of Alk1, Eng and Smad4 loss-of-function, the angiogenic factor and antagonistic ligand to the Tie2 receptor, angiopoietin-2 (Angpt2/ANG2), is transcriptionally elevated to trigger HHT vascular pathologies; ANG2 neutralization efficiently reduced AVM pathology in two HHT mouse models. In addition, loss of Alk1 signaling led to a robust and consistent transcriptional and signaling inhibition of Tek/Tie2. Together, these observations strongly support the working model that ANG2 is elevated and Tie2 signaling is repressed during the pathogenic process of AVM development in HHT. Moreover, the metabolic PI3K/Akt/mTOR pathway is deregulated in HHT to sustain AVM development, however its connection to ANG2 pro-AVM signals is unclear. Using mouse models of the different genetic forms of HHT and primary endothelial cells (ECs), we have obtained strong pilot data indicating that ANG2-Tie2 deregulations, working in concert with enhanced FoxO1 transcriptional activity and sequential overactivation of the mTOR pathway via CXCR4 chemokine signaling, drive HHT phenotypes. The central objective of this application is to answer 3 fundamental questions: 1) how does ANG2 elevation and Tie2 signaling repression direct AVM pathogenesis, 2) what is the mechanism by which mTOR overactivation is controlled by ANG2-Tie2 signaling deregulations and 3) are approaches targeting ANG2 and the newly identified ANG2-regulated pathogenic signaling cascade universally effective in treating HHT vascular pathologies? We will address these topics by testing the following specific aims: 1) Assess ANG2 and Tie2 signaling deregulations in the most physiologically affected organs and determine if ANG2 inhibition universally blocks vascular pathologies in HHT mouse models; 2) Determine FoxO1 contributions to ANG2 and CXCR4 elevations and HHT vascular pathologies; and 3) Test if TGF-beta-Tie2- FoxO1-mediated CXCR4 elevations drive mTOR activation. These studies will advance our mechanistic understanding of AVM pathogenesis and uncover new potential targets for treating of HHT.

项目概要 遗传性出血性毛细血管扩张症 (HHT) 是一种血管遗传性疾病，其特征是增大、渗漏 小血管（毛细血管扩张）以及动脉和静脉之间不适当的脆弱连接，称为 动静脉畸形（AVM）。 HHT 患者在主要器官的特定子集中出现 AVM，这 可能破裂导致严重出血和贫血，以及动脉瘤、中风甚至死亡。原因 HHT 与转化生长因子-β (TGF-β) 信号通路有关，超过 90% 的患者 激活素受体样激酶 1 (Acvrl1/Alk1) 或内皮糖蛋白出现杂合功能丧失突变 (Eng) 辅助受体，或下游转录因子，Smad 相关蛋白 4 (Smad4)。尽管知道 致病突变，我们对直接 TGF-β 下游的理解仍然存在重大差距 负责 HHT 病理的信号传导成分。此外，目前还没有治疗 HHT 的方法。我们 发现 Alk1、Eng 和 Smad4 功能丧失的直接下游，血管生成因子和 Tie2 受体的拮抗配体血管生成素-2 (Angpt2/ANG2) 在转录上升高以触发 HHT 血管病变； ANG2 中和有效减少了两种 HHT 小鼠模型中的 AVM 病理。 此外，Alk1 信号传导的缺失导致了强而一致的转录和信号传导抑制。 泰克/领带2。总之，这些观察结果强烈支持 ANG2 升高且 Tie2 的工作模型 HHT 中 AVM 发生的致病过程中信号传导受到抑制。此外，代谢 PI3K/Akt/mTOR 通路在 HHT 中解除管制以维持 AVM 发育，但其与 ANG2 的联系 pro-AVM 信号尚不清楚。使用 HHT 和原代内皮细胞不同遗传形式的小鼠模型 细胞（EC），我们已经获得了强有力的试点数据，表明 ANG2-Tie2 放松管制，与 通过 CXCR4 增强 FoxO1 转录活性和 mTOR 通路的连续过度激活 趋化因子信号传导，驱动 HHT 表型。该应用程序的中心目标是回答 3 个基本问题 问题：1）ANG2 升高和 Tie2 信号传导抑制如何指导 AVM 发病机制，2）什么是 通过 ANG2-Tie2 信号解除调节来控制 mTOR 过度激活的机制，3) 针对 ANG2 和新发现的 ANG2 调节的普遍致病信号级联的方法 治疗 HHT 血管病变有效吗？我们将通过测试以下具体内容来解决这些主题 目标：1) 评估受生理影响最严重的器官中 ANG2 和 Tie2 信号传导失调情况，以及 确定 ANG2 抑制是否普遍阻断 HHT 小鼠模型中的血管病理； 2) 确定FoxO1 对 ANG2 和 CXCR4 升高以及 HHT 血管病理的影响； 3) 测试 TGF-β-Tie2- FoxO1 介导的 CXCR4 升高驱动 mTOR 激活。这些研究将推进我们的机制 了解 AVM 发病机制并发现治疗 HHT 的新潜在靶点。