Erasing ill features of arterial endothelial cells in hereditary hemorrhagic telangiectasia

项目摘要 血管疾病的治疗进展可能具有深远的公共利益。动静脉畸形 动静脉畸形（AVM）是遗传性出血性毛细血管扩张症（HHT）的共同特征，并导致高生命风险。 危险的并发症先进的研究表明，激活素受体样突变的功能丧失， 激酶1（ALK 1）与HHT 2型（HHT 2）相关，小鼠中ALK 1基因缺失导致AVM。先前 研究还揭示ALK 1主要在动脉内皮细胞（EC）中表达。但据 不清楚ALK 1缺乏是否会导致动脉EC获得导致AVM的不良特征。了近现代 建议，我们已经获得的初步数据表明，新兴的淋巴管内皮细胞的特点， 通过诱导小鼠双微体2（MDM2）在动脉EC中的表达是以前未知的机制， 血管内皮细胞ALK 1缺乏的AVM，我们表明，消除这些不需要的方法， 特征减少AVM。因此，我们假设ALK 1缺乏会升高MDM2，从而导致AVM 通过诱导动脉EC中的淋巴管内皮特征，并且MDM2抑制被消除， 这些特点，以减少AVM。在具体目标1中，我们将阐明动脉粥样硬化的机制。 MDM2诱导作为内皮ALK 1缺乏症中AVM的致病因素。具体目标2： 确定动脉MDM 2诱导对人HHT 2的贡献。在具体目标3中，我们将确定 限制MDM2可减少内皮ALK 1缺陷小鼠中的AVM。没有基本的医疗手段， 预防或减少HHT2患者的AVM。在这个提议中，我们发现了一种新的机制，揭示了 由ALK 1缺陷驱动的动脉EC中出现的不需要的特征，以及具有这些特征的动脉EC 特征导致AVM。我们确定了一种化合物，并提出了一种新的治疗模式，旨在 通过消除动脉EC的这些不良特征来改善AVM。如果成功，我们提出的研究将 揭示了HHT 2动脉EC改变的机制基础，并提供了新的见解 治疗干预的机会。

PROJECT SUMMARY Therapeutic advances in vascular disease may have far-reaching public benefits. Arteriovenous malformations (AVMs) are the common feature of hereditary hemorrhagic telangiectasia (HHT) and cause the high risk of life- threatening complications. Advanced studies have shown that loss function of mutations in activin receptor-like kinase 1 (ALK1) are linked to HHT type 2 (HHT2) and ALK1 gene deletion in mice causes AVMs. Previous studies also reveal that ALK1 is predominantly expressed in arterial endothelial cells (ECs). However, it is unknown if ALK1 deficiency allows arterial ECs to acquire ill characteristics resulting in AVMs. In present proposal, we have obtained preliminary data to suggest that the emerging lymphatic endothelial characteristics in arterial ECs through the induction of mouse double minute 2 (MDM2) is previously unknown mechanism of AVMs in endothelial ALK1 deficiency, and we show that the approaches of erasing these undesired characteristics reduce AVMs. Therefore, we hypothesize that ALK1 deficiency elevates MDM2 to cause AVMs through the induction of lymphatic endothelial characteristics in arterial ECs, and MDM2 inhibition abolishes these characteristics to reduce AVMs. In specific Aim 1, we will elucidate the mechanism underlying arterial MDM2 induction as a causative factor of AVMs in endothelial ALK1 deficiency. In specific Aim 2, we will determine the contribution of arterial MDM2 induction to human HHT2. In specific Aim 3, we will determine if limiting MDM2 reduces AVMs in endothelial ALK1-deficient mice. There is no primary medical treatment to prevent or reduce the AVMs of HHT2 patients. In this proposal, we discover a novel mechanism that reveals the unwanted characteristics emerging in arterial ECs driven by ALK1 deficiency, and arterial ECs with these characteristics cause AVMs. We identify a compound and propose a novel treatment paradigm aiming to ameliorate AVMs by erasing these ill characteristics from arterial ECs. If succussed, our proposed studies would reveal the mechanistic underpinnings of alterations in arterial ECs of HHT2 and provide insight into new opportunities for therapeutic interventions.