LRP1 and endothelial function

LRP1 和内皮功能

基本信息

批准号：
9273589
负责人：
Xinchun Pi
金额：
$ 39.63万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9273589
关键词：
Alteplase Apolipoprotein E Arterial Fatty Streak Atherosclerosis Binding Biological Models Biological Process Blood Vessels Cardiovascular Diseases Cardiovascular system Cell Nucleus Complex Data Defect Development Disease Dyslipidemias Eicosanoids Endocytosis Endothelial Cells Endothelium Event Family Fatty Acids Gene Targeting Genetic Transcription Glucose Growth Health Homeostasis Hypolipidemic Agents Hypoxia In Vitro Inflammation Injury Investigation Knock-out Knowledge LDL-Receptor Related Protein 1 Lead Ligand Binding Ligand Binding Domain Ligands Lipopolysaccharides Low Density Lipoprotein Receptor Maintenance Malignant Neoplasms Mediating Membrane Modeling Molecular Conformation Mus Oxygen PPAR alpha PPAR gamma PPAR-beta Pathologic Peripheral Vascular Diseases Peroxisome Proliferator-Activated Receptors Physiological Play RXR Receptor Signaling Regulation Retinal Neovascularization Role Signal Pathway Signal Transduction Stimulus Stress Support Groups Transcriptional Activation Vascular Endothelium Vasomotor Zebrafish angiogenesis clinical application extracellular fatty acid metabolism in vivo insulin sensitizing drugs knock-down lipid metabolism member migration new therapeutic target novel public health relevance receptor response retinal angiogenesis theories therapeutic target

项目摘要

DESCRIPTION (provided by applicant): The maintenance of endothelial functions is essential for vascular homeostasis, vascular development, angiogenesis and vasomotor tone. The dysregulation of the vascular endothelium in response to vascular injury and stress contributes to many cardiovascular diseases such as inflammation, atherosclerosis, peripheral vascular disease and cancer. The peroxisome proliferator-activated receptors (PPARs) family, important regulators of glucose and fatty acid metabolism, is one important signaling pathway involved in regulating pathophysiologic functions such as angiogenesis, inflammation and atherosclerosis. The PPAR family consists of three ligand-activated receptors: PPARα, PPARß/δ and PPARγ, all of which are expressed in endothelial cells. Although the importance of PPAR signaling in the endothelium is now recognized, an accurate understanding of the mechanisms responsible for their pathophysiologic regulation remains largely unknown. Recently I identified LRP1 (low density lipoprotein receptor-related protein 1) as a novel regulator of PPAR signaling. LRP1 is a heterodimer composed of a 515-kDa α chain (LRP1α) possessing four extracellular ligand binding domains and an 85-kDa membrane-anchored intracellular ß chain known for transducing signals. LRP1 is a multifunctional member of the LDL receptor family, impacting a variety of biological processes such as lipid metabolism, endocytosis and signal transduction. However, the role of LRP1 in endothelium is almost unknown. Our recent preliminary data demonstrate that LRP1ß interacts with PPARß/δ in the nucleus and regulates its transcriptional activity, suggesting that LRP1 acts as a novel regulator of PPARs in endothelial cells. In addition, we observed that LRP1 is induced by hypoxia and is a novel regulator of Bmp signaling pathway through its association with the extracellular modulator-Bmper (Bmp-binding endothelial cell precursor-derived regulator), which itself plays an essential role in the regulatin of endothelial functions such as angiogenesis and atherosclerosis. Moreover, we observe that LRP1 regulates endothelial growth, migration, inflammation and tubulogenesis in vitro, zebrafish vascular development and mouse retinal angiogenesis in vivo. These observations lead us to hypothesize that LRP1 acts as an essential regulator of endothelial function through its integration of signaling responses to a diverse range of stimuli to activate downstream effectors such as PPARs. The aims include (1) investigate the role of LRP1 in the regulation of endothelial signaling events; (2) elucidate the effects of LRP1 on endothelial cellular events; (3) study the effects of LRP1 deficiency on angiogenesis and atherosclerosis in vivo. The knowledge gained from this proposal will provide novel therapeutic targets and strategies for treating angiogenesis-dependent diseases and atherosclerosis.

描述（由适用提供）：内皮功能的维持对于血管稳态，血管发育，血管生成和血管舒张肌张力至关重要。血管内皮造成血管损伤和压力的失调导致许多心血管疾病，例如感染，动脉粥样硬化，周围血管疾病和癌症。现在认识到PPAR信号传导在森植物中的重要性，但过氧化物体增生剂激活受体（PPAR）家族（PPAR）家族的重要性，但对负责机理机制的机制的机制进行了准确的理解。 LRP1是由具有四个具有四个细胞外配体结合结构域的515-KDA链（LRP1α）组成的异二聚体和一个85 kDa膜锚定的细胞内ß链，该链已知用于传输信号。 LRP1是LDL受体家族的多功能成员，影响了多种生物学过程，例如脂质代谢，内吞作用和信号转导。但是，LRP1在山上的作用几乎是未知的。我们最近的初步数据表明，LRP1ß与核中的PPARß/δ相互作用，并调节其转录活性，这表明LRP1在森植物细胞中充当了PPARS的新调节剂。此外，我们观察到LRP1是由缺氧诱导的，并且是BMP信号通路的新型调节剂，其与细胞外调节剂-BMPER（BMP结合内皮细胞前体衍生的调节剂）的关联本身在诸如Angiogensosis和AneThersossis的内皮功能中起着重要作用。此外，我们观察到LRP1在体外调节体外内皮生长，迁移，注射和结核病，斑马鱼血管发育和小鼠定期的体内血管生成。这些观察结果使我们假设LRP1通过整合对潜水员刺激范围的信号反应以激活下游效应（例如PPAR），从而成为内皮功能的必不可少的调节剂。目的包括（1）研究LRP1在调节内皮信号事件中的作用；（2）阐明LRP1对内皮细胞事件的影响；（3）研究LRP1缺乏对体内血管生成和动脉粥样硬化的影响。从该建议中获得的知识将为治疗血管生成依赖性疾病和动脉粥样硬化提供新的治疗靶标和策略。