LRP1 and endothelial function

LRP1 和内皮功能

• 批准号: 8705573
• 负责人: Xinchun Pi
• 金额: $ 11.14万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8705573
• 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; Differentiation and Growth; Disease; Dyslipidemias; Eicosanoids; Endocytosis; Endothelial Cells; Endothelium; Event; Family; Fatty Acids; Functional disorder; Gene Targeting; 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; Mus; Oxygen; Peripheral Vascular Diseases; Peroxisome Proliferator-Activated Receptors; Physiological; Plasminogen Activator; Play; RXR; Receptor Activation; Receptor Signaling; Regulation; Retinal Neovascularization; Role; Signal Pathway; Signal Transduction; Stimulus; Stress; Support Groups; Vascular Endothelium; Vasomotor; Work; Zebrafish; angiogenesis; clinical application; extracellular; fatty acid metabolism; in vivo; insulin sensitizing drugs; interest; lipid metabolism; member; migration; mouse development; new therapeutic target; novel; public health relevance; receptor; response; retinal angiogenesis; theories; therapeutic target

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: PPAR¿, PPAR¿/¿ and PPAR¿, 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 ¿ chain (LRP1¿) possessing four extracellular ligand binding domains and an 85-kDa membrane-anchored intracellular ¿ 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 LRP1¿ interacts with PPAR¿/¿ 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。过氧化物体增殖物激活受体（PPAR）家族，葡萄糖和脂肪酸代谢的重要调节剂，是一种重要的信号传导途径，涉及调节病理生理功能，例如血管生成，炎症和动脉粥样硬化。 PPAR家族由三个配体激活的受体组成：PPAR¿，PPAR¿ /®和PPAR？所有这些都在内皮细胞中表达。尽管现在认识到PPAR信号在内皮中的重要性，但对负责其病理生理调节的机制的准确理解在很大程度上尚不清楚。最近，我将LRP1（低密度脂蛋白受体相关蛋白1）确定为PPAR信号传导的新调节剂。 LRP1是由具有四个具有四个细胞外配体结合结构域的515 kDa（LRP1？）组成的异二聚体，以及一个85 kDa膜锚定的细胞内»链链链，已知用于传输信号的链。 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在内皮中的作用几乎是未知的。我们最近的初步数据表明，LRP1与PPAR®相互作用，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因子，通过其与细胞外调节剂相关联，它与BMP结合细胞前体细胞前体的调节器中的最终范围的作用，该角色在其本身中的重要作用，该作用是该角色的一部分。血管生成和动脉粥样硬化。此外，我们观察到LRP1在体外调节体外内皮生长，迁移，感染和微管发生，斑马鱼血管发育以及小鼠在体内的残留血管生成。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。