A Novel Role for cMyc in Vascular Homeostasis

cMyc 在血管稳态中的新作用

• 批准号: 10449636
• 负责人: CLAUDIA OLIVEIRA RODRIGUES
• 金额: $ 3.87万
• 依托单位: FLORIDA ATLANTIC UNIVERSITY
• 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 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10449636
• 关键词: Novel; Role; cMyc; Vascular; Homeostasis

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稳定中起着重要作用。内皮功能障碍， 以血管中的表型和血液动力学变化为特征，是心血管疾病的早期预测因子。 疾病，全球死亡的主要原因。衰老过程中对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 心肌梗死和中风等事件。因此，更好地了解分子机制 调节血管老化和炎症的蛋白质，对于控制心血管疾病至关重要。的 内皮通过控制细胞因子的表达和粘附在炎症中起关键作用 参与吸引、粘附和浸润炎性细胞的分子。与系统性 由于血管网的分布，内皮细胞是衰老中炎症介质的潜在来源 和慢性炎症性疾病。虽然促炎分子的身份是众所周知的， 控制其表达的机制是复杂和多因素的。因此，需要更多的研究来 鉴定调节衰老促炎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来保持内皮细胞的稳态，从而防止血管内皮细胞的凋亡。 炎症和相关的心血管疾病。我们提出的研究目标是了解如何 内皮cMyc调节血管老化和炎症。我们小组最近的工作发现了一种新的 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 初步研究表明，在经历复制性炎症的人内皮细胞中，cMyc表达下降， 衰老，并且这种现象与炎症标志物的表达增加有关。我们 在内皮细胞谱系中特异性过表达cMyc的小鼠中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cMyc是一个重要的调节因子的核心假设。 衰老相关的血管炎症。在目标1中，我们将确定cMyc如何调节血管老化 使用特异性在内皮细胞中条件性缺失c-Myc的野生型和基因工程成年小鼠， 脉在目标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中描述的。在目标3中，我们将鉴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个目的，将结果与市售内皮细胞进行比较 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靶点。