A Novel Role for cMyc in Vascular Homeostasis

cMyc 在血管稳态中的新作用

• 批准号: 9383491
• 负责人: CLAUDIA OLIVEIRA RODRIGUES
• 金额: $ 39.15万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-10 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9383491
• 关键词: Acute; Adhesions; Adult; Age; Aging; Alpha Cell; 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; Disease; Endothelial Cells; Endothelium; Event; Fibrosis; Gene Expression Profiling; Gene Targeting; 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; cytokine; endothelial dysfunction; genetic manipulation; hemodynamics; in vivo; inflammatory marker; inhibitor/antagonist; knock-down; mouse model; normal aging; novel; overexpression; prevent; response; senescence; therapeutic target; transcription factor; vascular inflammation

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内环境平衡中起着重要作用。内皮功能障碍， 以血管的表型和血流动力学变化为特征，是心血管疾病的早期预测指标 疾病是全球主要的死亡原因。衰老过程中对内皮的慢性氧化性损伤导致 内皮细胞衰老和发展为促炎表型，增加了心血管疾病的风险 事件，如心肌梗塞和中风。因此，更好地理解了分子机制 调节血管老化和炎症，对控制心血管疾病至关重要。这个 内皮细胞通过控制细胞因子的表达和黏附在炎症中发挥关键作用 参与炎症细胞的吸引、黏附和渗透的分子。与系统性的 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 以及慢性炎症性疾病。尽管促炎分子的特性是众所周知的，但 控制其表达的机制是复杂的和多因素的。因此，需要更多的研究来 识别调节衰老促炎作用的细胞介质以及中心分子和途径 在正常老化和病理条件下的反应。 我们的长期目标是开发干预措施，以保持内皮细胞的动态平衡，从而防止血管 炎症和相关的心血管疾病。我们提议的研究的目标是了解 内皮细胞cMyc调节血管衰老和炎症。我们小组最近的工作确定了一部小说 转录因子cMyc作为血管衰老和炎症的潜在调节因子的作用。我们的 初步研究表明，人内皮细胞在复制过程中cMyc的表达下降 这种现象与炎症标记物的表达增加有关。我们 对内皮细胞系高表达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 在不同的器官中老化。这些发现支持cMyc是一个重要的调节因子的中心假说。 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 用野生型和转基因成年小鼠有条件地删除内皮细胞中的c-Myc 血统。在目标2中，我们将使用小鼠模型来研究cMyc在血管炎症中的作用 在目标1中，我们将确定在血管老化中起作用的cMyc下游靶基因 和炎症。对于提出的3个目标，结果将与商业上可获得的内皮细胞进行比较 来自年轻和年长的捐赠者。完成这些目标将确定新的机制和潜在的治疗方法 控制血管老化和炎症的靶点。