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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：
10413737
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/10413737
关键词：
ACVRL1 gene Arteries Arteriovenous malformation Binding Blood Vessels Bypass Cell Differentiation process Cell Line Cell Proliferation ChIP-seq Characteristics DNA Binding DNA sequencing Data Double Minutes Endothelial Cells Endothelium Gene Deletion Genetic Transcription Hereditary hemorrhagic telangiectasia Homeobox Human In Vitro Lead 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 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 strategies 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.

项目总结