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.

项目摘要 遗传性出血性毛细血管扩张（HHT）是一种血管遗传疾病，其特征是泄漏肿大 小血管（Telangiectasias）和动脉与静脉之间的不适当，脆弱的连接 动脉畸形（AVM）。 HHT患者在特定的主要器官中发展AVM， 会破裂会导致严重的出血和贫血，以及动脉瘤，中风甚至死亡。原因 HHT与转化的生长因子-BETA（TGF-BETA）信号通路有关，患者超过90％ 在激活素受体样激酶1（ACVRL1/ALK1）或内og胶中表现出杂合丧失功能突变 （ENG）共受体或下游转录因子SMAD相关蛋白4（SMAD4）。尽管知道 因果突变，我们对下游TGF-beta的理解仍然存在很大的差距 负责HHT病理的信号传导成分。此外，目前无法治愈HHT。我们 已经发现，直接下游ALK1，ENG和SMAD4功能丧失，血管生成因子和 对TIE2受体Angiopoietin-2（Angpt2/Ang2）的拮抗配体在转录上升高至触发 HHT血管病理； Ang2中和有效降低了两个HHT小鼠模型中的AVM病理。 此外，ALK1信号的丢失导致了强大而一致的转录和信号抑制 TEK/TIE2。这些观察结果共同支持了Ang2升高和TIE2的工作模型 在HHT中AVM发育的致病过程中，信号被抑制。而且，代谢 pi3k/akt/mtor途径在HHT中被放松以维持AVM开发，但是它与Ang2的联系 Pro-AVM信号尚不清楚。使用HHT和主要内皮的不同遗传形式的小鼠模型 细胞（EC），我们获得了强大的试点数据，表明Ang2-Tie2放松调节，与 通过CXCR4增强了FOXO1转录活性和MTOR途径的顺序过度激活 趋化因子信号传导，驱动HHT表型。该应用程序的核心目的是回答3个基本 问题：1）ANG2高程和TIE 2信号抑制如何直接AVM发病机理，2）什么是什么 MTOR过度活化通过Ang2-Tie2信号传导控制和3）的机制是 靶向ANG2和新鉴定的ANG2调节的致病信号级联的方法普遍 有效治疗HHT血管病理？我们将通过测试以下特定来解决这些主题 目的：1）在生理影响最大的器官和 确定ANG2抑制是否普遍阻止HHT小鼠模型中的血管病变； 2）确定FOXO1 对ANG2和CXCR4高程以及HHT血管病理的贡献； 3）测试是否tgf-beta-tie2- FOXO1介导的CXCR4高程驱动MTOR激活。这些研究将提高我们的机械 了解AVM发病机理并发现治疗HHT的新潜在靶标。