A Novel Role for cMyc in Vascular Homeostasis

cMyc 在血管稳态中的新作用

基本信息

批准号：
10159716
负责人：
CLAUDIA OLIVEIRA RODRIGUES
金额：
$ 2.02万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-12 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10159716
关键词：
Acute Adhesions Adult Age Aging American Atherosclerosis Biochemical Biological Assay Biophysics Blood Vessels Cardiovascular Diseases Cause of Death Cell Adhesion Molecules Cell Aging Cell Cycle Cell Lineage Cells ChIP-seq Chronic Complex Coronary heart disease Data Development Endothelial Cells Endothelium Event Fibrosis Gene Expression Profiling Genes Genetic Engineering Goals Homeostasis Human Immunoprecipitation In Vitro Infiltration Inflammation Inflammation Mediators Inflammatory Inflammatory Response Injury Intervention Maintenance Malignant Neoplasms Mediating Mediator of activation protein Mesenchymal Molecular Mus Myocardial Infarction Nature Oncogenic Organ Oxidants Pathologic Pathway interactions Phenotype Play Prevention Publishing Reporter Repression Role Source Stress Stroke Testing Time Tissues Wild Type Mouse Work aged c-myc Genes cardiovascular risk factor chronic inflammatory disease cytokine endothelial dysfunction genetic manipulation hemodynamics in vivo inflammatory marker inhibitor/antagonist knock-down mouse model normal aging novel overexpression preservation prevent response senescence therapeutic target transcription factor vascular inflammation

项目摘要

Endothelial cells play an important role in the maintenance of tissue homeostasis. Endothelial dysfunction, characterized by phenotypic and hemodynamic changes in blood vessels, is an early predictor of cardiovascular disease, the leading cause of death worldwide. Chronic oxidant injury to the endothelium during aging leads to endothelial senescence and development of a pro-inflammatory phenotype, increasing the risk of cardiovascular events such as myocardial infarction and stroke. Therefore, better understanding of the molecular mechanisms that regulate vascular aging and inflammation, is essential for the control of cardiovascular disease. The endothelium plays a critical role in inflammation by controlling the expression of cytokines and adhesion molecules involved in attraction, adhesion and infiltration of inflammatory cells. Consistent with the systemic distribution of the vascular network, endothelial cells are a potential source of inflammatory mediators in aging and chronic-inflammatory diseases. Although the identity of pro-inflammatory molecules is well known, the mechanisms that control their expression are complex and multifactorial. Therefore, more studies are needed to identify cellular mediators as well as central molecules and pathways that regulate senescence pro-inflammatory response under normal aging and pathological conditions. Our long-term goal is to develop interventions to preserve endothelial homeostasis, thus preventing vascular inflammation and associated cardiovascular disease. Our goal with the proposed study is to understand how endothelial cMyc regulates vascular aging and inflammation. Recent work from our group have identified a novel role for the transcription factor cMyc as a potential regulator of vascular senescence and inflammation. Our preliminary studies indicate that cMyc expression declines in human endothelial cells undergoing replicative senescence, and that this phenomenon is associated with increased expression of inflammation markers. We performed gene expression profiling studies in mice overexpressing cMyc specifically in endothelial cell lineage and observed a reduction in the expression of the senescence marker p21 and pro-inflammatory mediators with aging in different organs. These findings support the central hypothesis that cMyc is an essential regulator of senescence-associated vascular inflammation. In Aim 1, we will determine how cMyc regulates vascular aging using wild-type and genetically engineered adult mice with conditional deletion of c-Myc specifically in endothelial lineage. In Aim 2, we will investigate the contribution of cMyc to vascular inflammation using the mouse model described in Aim 1. In Aim 3, we will identify cMyc downstream target genes that play a role in vascular aging and inflammation. For the 3 aims proposed, results will be compared to commercially available endothelial cells from young and aged donors. Completion of these aims will define novel mechanisms and potential therapeutic targets that control vascular aging and inflammation.

内皮细胞在维持组织稳态中发挥重要作用。内皮功能障碍，以血管表型和血流动力学变化为特征，是心血管疾病的早期预测因子疾病，是全世界死亡的主要原因。衰老过程中内皮细胞的慢性氧化损伤导致内皮衰老和促炎表型的发展，增加心血管疾病的风险心肌梗塞和中风等事件。因此，更好地了解分子机制调节血管老化和炎症，对于控制心血管疾病至关重要。这内皮通过控制细胞因子的表达和粘附在炎症中发挥关键作用参与炎症细胞吸引、粘附和浸润的分子。与系统一致血管网络的分布，内皮细胞是衰老过程中炎症介质的潜在来源和慢性炎症性疾病。尽管促炎分子的身份众所周知，控制其表达的机制是复杂且多因素的。因此，需要更多的研究识别细胞介质以及调节衰老促炎症的中心分子和途径正常衰老和病理条件下的反应。我们的长期目标是开发干预措施来维持内皮稳态，从而预防血管疾病炎症和相关的心血管疾病。我们提出的研究的目标是了解如何内皮细胞 cMyc 调节血管老化和炎症。我们小组最近的工作发现了一部小说转录因子 cMyc 作为血管衰老和炎症的潜在调节剂的作用。我们的初步研究表明，在复制过程中人内皮细胞中 cMyc 表达下降衰老，并且这种现象与炎症标志物表达增加有关。我们对内皮细胞谱系中过度表达 cMyc 的小鼠进行基因表达谱研究并观察到衰老标志物 p21 和促炎介质的表达减少不同器官的衰老。这些发现支持了中心假设，即 cMyc 是一个重要的调节因子衰老相关的血管炎症。在目标 1 中，我们将确定 cMyc 如何调节血管衰老使用野生型和基因工程成年小鼠，条件性删除内皮细胞中的 c-Myc 血统。在目标 2 中，我们将使用小鼠模型研究 cMyc 对血管炎症的贡献目标 1 中描述。在目标 3 中，我们将鉴定在血管老化中发挥作用的 cMyc 下游靶基因和炎症。对于提出的 3 个目标，结果将与市售内皮细胞进行比较来自年轻和年老的捐赠者。这些目标的完成将定义新的机制和潜在的治疗方法控制血管老化和炎症的目标。