Roles of neuropilin-1 in endothelial cell dysfunction

Neuropilin-1 在内皮细胞功能障碍中的作用

• 批准号: 10474886
• 负责人: Ying Wang
• 金额: $ 39.15万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-06 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10474886
• 关键词: Roles; neuropilin; endothelial; cell; dysfunction

PROJECT SUMMARY/ABSTRACT Heart failure with preserved ejection fraction (HFpEF) affects more than 3 million adults of the United States and has no effective therapy. The promising effect of general strategies for improving endothelial cell (EC) function in HFpEF patients has highlighted the crucial roles of EC dysfunction in the disease pathogenesis. However, the molecular mechanism of EC dysfunction and how it contributes to the pathogenesis of HFpEF are still poorly understood. A recent patient study identified serum neuropilin-1 (NRP1) as a prognostic marker in HFpEF patients. Our preliminary data indicate that endothelial NRP1 is increased in the cardiac tissues of murine HFpEF models and mice deficient of endothelial NRP1 show improved EC and cardiac diastolic functions in these models. Tumor necrosis factor-α (TNFα) is a major inducer of EC dysfunction and associates with the disease progression of HFpEF. Our preliminary data suggest that knockdown of NRP1 reduces TNFα-induced expression of adhesion molecules but enhances the levels of endothelial nitric oxide synthase (eNOS) in ECs. Computational docking model and protein binding assay collectively indicate the direct interaction between NRP1 and TNFα. Based on these results, this project will test the central hypothesis that endothelial NRP1, acting as a novel co-receptor with TNFR, leads to the pathogenesis of HFpEF by increasing cardiac inflammation and impairing myocardial nitric oxide bioavailability. Two Specific Aims are proposed: Aim 1: Delineate the crosstalk between NRP1 and TNFα/TNFR in EC dysfunction. We will characterize the interaction between NRP1 and TNFα/TNFR using microplate-based binding assay and cultured ECs. The role of NRP1 in TNFα-induced EC dysfunction will be examined in both mouse and zebrafish endothelial cell specific NRP1 knockout models. Aim 2: Reveal the role of endothelial NRP1 in the pathogenesis of HFpEF. We will use mouse HFpEF models to investigate how endothelial NRP1 cooperates with TNFR1 to control the disease initiation and progression of HFpEF.

项目总结/摘要 射血分数正常的心力衰竭（HFpEF）影响着美国300多万成年人 并且没有有效的治疗方法。改善内皮细胞（EC）的一般策略的有希望的效果 HFpEF患者的EC功能的研究突出了EC功能障碍在疾病发病机制中的关键作用。 然而，EC功能障碍的分子机制及其如何参与HFpEF的发病机制尚不清楚。 仍然知之甚少。最近的一项患者研究将血清神经纤毛蛋白-1（NRP 1）确定为预后标志物 在HFpEF患者中。我们的初步数据表明，内皮NRP 1在心肌组织中增加， 鼠HFpEF模型和内皮NRP 1缺陷小鼠显示改善的EC和心脏舒张功能 在这些模型中。肿瘤坏死因子-α（TNFα）是EC功能障碍的主要诱导因子， 与HFpEF的疾病进展相关。我们的初步数据表明，NRP 1的敲除 减少TNFα诱导的粘附分子表达，但增加内皮一氧化氮水平 eNOS合成酶（eNOS）。计算对接模型和蛋白质结合试验共同表明， NRP 1和TNFα之间的直接相互作用。基于这些结果，本项目将检验中心假设 内皮NRP 1作为TNFR的一种新的共受体，通过以下途径导致HFpEF的发病机制： 增加心脏炎症和损害心肌一氧化氮生物利用度。 目的1：阐明EC中NRP 1与TNFα/TNFR之间的相互作用 功能障碍我们将使用基于微孔板的方法来表征NRP 1和TNFα/TNFR之间的相互作用。 结合测定和培养的EC。NRP 1在TNFα诱导的EC功能障碍中的作用将在两种研究中进行研究。 小鼠和斑马鱼内皮细胞特异性NRP 1敲除模型。目的2：揭示内皮细胞在血管生成中的作用 NRP 1在HFpEF发病机制中的作用我们将使用小鼠HFpEF模型来研究内皮NRP 1 与TNFR 1协同控制HFpEF的疾病发生和进展。