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

• 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
• 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

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.

项目总结 血管疾病的治疗进展可能会对公众产生深远的影响。动静脉畸形 (动静脉畸形)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。高级研究表明，激活素受体样突变的功能丧失 激酶1(ALK1)与HHT2型(HHT2)相关，小鼠的ALK1基因缺失会导致动静脉曲张。上一首 研究还表明，ALK1主要表达在动脉内皮细胞(ECs)。然而，它是 ALK1缺乏是否使动脉内皮细胞获得导致动静脉动静脉畸形的不良特征尚不清楚。现在 建议，我们已经获得了初步数据，表明出现的淋巴管内皮细胞特征 在动脉内皮细胞中通过诱导小鼠双分钟2(MDM2)的作用机制尚不清楚 动静脉畸形在内皮细胞ALK1缺乏症中的作用，我们展示了消除这些不良反应的方法 这些特征减少了动静脉动静脉畸形。因此，我们假设ALK1缺乏会导致MDM2升高，从而导致脑动静脉畸形 通过诱导动脉内皮细胞的淋巴管内皮细胞特性，并取消对MDM2的抑制 这些特点降低了动静脉动静脉畸形。在具体目标1中，我们将阐明动脉的发病机制。 MDM2诱导是内皮性ALK1缺乏症动静脉动静脉畸形的致病因素。在具体目标2中，我们将 确定动脉MDM2诱导对人HHT2的贡献。在具体目标3中，我们将确定是否 限制MDM2可减少血管内皮细胞ALK1缺陷小鼠的AVM。没有基本的医疗服务 预防或减少HHT2患者的脑动静脉畸形。在这个提议中，我们发现了一种新的机制，它揭示了 由ALK1缺乏驱动的动脉内皮细胞出现不想要的特征，以及具有这些特征的动脉内皮细胞 特征导致动静脉动静脉畸形。我们确定了一种化合物，并提出了一种新的治疗模式，旨在 通过从动脉内皮细胞中清除这些不良特征来改善动静脉曲张。如果简明扼要，我们提议的研究将 揭示HHT2动脉内皮细胞改变的机制基础，并提供对新的 治疗干预的机会。