Erasing ill features of arterial endothelial cells in hereditary hemorrhagic telangiectasia

消除遗传性出血性毛细血管扩张症中动脉内皮细胞的不良特征

基本信息

批准号：
10586071
负责人：
Yucheng Yao
金额：
$ 39万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
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/10586071
关键词：
ACVRL1 gene Activin A type II receptor Arteries Arteriovenous malformation Binding Blood Vessels Bypass Cell Differentiation process Cell Line Cell Proliferation Characteristics DNA Binding DNA sequencing Data Double Minutes Endothelial Cells Endothelium Gene Deletion Genetic Transcription Hereditary hemorrhagic telangiectasia Homeobox Human In Vitro Lesion Life Link Lymphatic Endothelium Medical Mus Normal tissue morphology Organ Patients Persons Physiologic arteriovenous anastomosis Public Health Shunt Device Specificity Telangiectasis Testing Therapeutic Therapeutic Intervention VEGFC gene Vascular Diseases Vascular Endothelial Growth Factor C Vascular Endothelial Growth Factor Receptor-3 Veins Wild Type Mouse activin receptor-like kinase 1 capillary bed chromatin immunoprecipitation high risk in vivo inhibitor insight loss of function mutation mouse model novel novel therapeutic intervention prevent repaired

项目摘要

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.

项目概要血管疾病的治疗进展可能会产生深远的公共利益。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，并导致生命的高风险 - 威胁并发症。先进的研究表明，激活素受体样突变的功能丧失激酶 1 (ALK1) 与 HHT 2 型 (HHT2) 相关，小鼠中 ALK1 基因缺失会导致 AVM。以前的研究还表明 ALK1 主要在动脉内皮细胞 (EC) 中表达。然而，它是尚不清楚 ALK1 缺乏是否会导致动脉 EC 获得不良特征，从而导致 AVM。目前建议，我们已经获得初步数据表明新兴的淋巴管内皮特征通过诱导小鼠双分钟 2 (MDM2) 在动脉 EC 中发挥作用是以前未知的机制内皮 ALK1 缺陷中的 AVM，我们展示了消除这些不需要的方法特性可减少 AVM。因此，我们假设 ALK1 缺陷会升高 MDM2 从而导致 AVM 通过诱导动脉 EC 中的淋巴管内皮特性，抑制 MDM2 消除这些特性可以减少 AVM。在具体目标 1 中，我们将阐明动脉粥样硬化的潜在机制。 MDM2 诱导是内皮 ALK1 缺陷中 AVM 的致病因素。在具体目标 2 中，我们将确定动脉 MDM2 诱导对人类 HHT2 的贡献。在具体目标 3 中，我们将确定是否限制 MDM2 可减少内皮 ALK1 缺陷小鼠的 AVM。没有基本的医疗方法可以治疗预防或减少 HHT2 患者的 AVM。在这个提案中，我们发现了一种新颖的机制，揭示了 ALK1 缺乏导致的动脉 EC 中出现不需要的特征，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范例，旨在通过消除动脉 EC 中的这些不良特征来改善 AVM。如果成功的话，我们提出的研究将揭示 HHT2 动脉 EC 变化的机制基础并提供新的见解治疗干预的机会。