Biphasic Regulation of Endothelial Transdifferentiation by Alcohol and Its Impact on Vascular Disease

酒精对内皮转分化的双相调节及其对血管疾病的影响

基本信息

批准号：
10771448
负责人：
EILEEN M. REDMOND
金额：
$ 45.89万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-20 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10771448
关键词：
Activities of Daily Living Affect Alcohol consumption Alcohols Arterial Fatty Streak Arteriosclerosis Basic Science Behavior Blood Vessels Blood flow Cardiovascular Diseases Cause of Death Cell Adhesion Molecules Cells Cessation of life Chronic Clinical Color Consumption Data Development Disease Progression Disease regression Dose Endothelial Cells Endothelium Foundations Guidelines Homeostasis Human Hyperplasia Hypoxia In Vitro Incidence Inflammation Inflammatory Knock-in Mouse Knock-out Knowledge Laboratory Study Lesion Medial Mediating Mesenchymal Modeling Molecular Morbidity - disease rate Myocardial Infarction Myofibroblast Pathologic Pathology Phase Phenotype Prevention Process Proliferating Published Comment Regulation Reporter Risk Factors Role Science Severities Shapes Signal Transduction Smooth Muscle Myocytes Stimulus Stroke Testing Vascular Diseases Vascular Smooth Muscle Work alcohol effect alcohol measurement antagonist arterial stiffness binge drinking cardiovascular health cell type cytokine disability drinking drinking behavior endothelial dysfunction epidemiology study gain of function improved in vivo interest intima media intimal medial thickening loss of function migration mimetics modifiable behavior mortality mouse model notch protein novel novel therapeutics protective effect response single-cell RNA sequencing transcriptomics transdifferentiation

项目摘要

Abstract Cardiovascular disease is the leading cause of death worldwide. Epidemiological studies indicate a biphasic association between alcohol and cardiovascular disease with frequent low-to-moderate consumption being protective, whereas heavy bingeing and chronic abuse is harmful. Currently lacking, however, is in-depth mechanistic knowledge of how different levels of alcohol impact arterial cells to ultimately dictate vessel pathology and disease progression. Most of the problems associated with cardiovascular disease begin with arteriosclerosis, a thickening and stiffening of the artery wall, that may progress to plaque development and blood flow blockage resulting in heart attack or stroke. Arteriosclerosis involves medial and intimal hyperplasia (i.e., intima-media thickening or IMT) due to the accumulation of ‘vascular smooth muscle-like’ a-SMA+ cells. Emerging evidence suggests that in response to injurious stimuli such as inflammation or disturbed flow, endothelial cells can transform into different cell types, especially myofibroblasts in a process known as endothelial-to-mesenchymal transition (EndMT), and thus contribute to intima-media thickening. Crucially, no information exists as to whether alcohol consumption, a common modifiable behavior and a known modulator of cardiovascular disease, might regulate endothelial transformation in this context, a question of considerable interest and the focus of our proposal. Based on our exciting preliminary data in human arterial cells and in a mouse model, we will use gain-and-loss of function approaches in vitro and in vivo, in combination with multi- color ‘Confetti’ reporter lineage tracing and single-cell RNA-sequencing analyses to test our hypothesis that alcohol has a biphasic effect on atherogenic stimuli-induced endothelial phenotypic transformation to differentially affect vessel homeostasis and arteriosclerosis and to elucidate the involvement of Notch in mediating these responses. Data generated will markedly increase our basic science understanding of how drinking affects cardiovascular disease, information that could be leveraged to inform novel treatments for this leading cause of morbidity and mortality.

抽象的流行病学研究表明，心血管疾病是世界范围内死亡的主要原因。经常低至中等饮酒量的酒精与心血管疾病之间的关联过度暴饮暴食和长期滥用是有害的，但目前缺乏深入的研究。关于不同水平的酒精如何影响动脉细胞最终控制血管的机械知识大多数与心血管疾病相关的问题都始于病理学和疾病进展。动脉硬化，动脉壁增厚和硬化，可能会发展为斑块形成和血流阻塞导致心脏病或中风，动脉硬化涉及内膜和内膜增生。（即内膜中层增厚或 IMT）是由于“血管平滑肌样”a-SMA+ 细胞的积累所致。新的证据表明，为了应对炎症或血流紊乱等有害刺激，内皮细胞可以转化为不同的细胞类型，尤其是肌成纤维细胞，这一过程称为内皮-间质转化（EndMT），从而导致内膜中层增厚，这一点至关重要。存在关于饮酒是否是一种常见的可改变行为以及已知的调节剂的信息心血管疾病，可能在这种情况下调节内皮转化，这是一个相当大的问题基于我们在人类动脉细胞和研究中令人兴奋的初步数据。小鼠模型，我们将在体外和体内使用功能获得和丧失的方法，并结合多种彩色“五彩纸屑”记者谱系追踪和单细胞 RNA 测序分析来检验我们的假设酒精对致动脉粥样硬化刺激诱导的内皮表型转化具有双相作用不同程度地影响血管稳态和动脉硬化，并阐明 Notch 在产生的数据将显着增加我们对如何进行基础科学的理解。饮酒会影响心血管疾病，这些信息可用于为此提供新的治疗方法发病率和死亡率的主要原因。