Formyl peptide receptor activation induces vascular plasticity and remodeling inhypertension

甲酰基肽受体激活诱导高血压血管可塑性和重塑

• 批准号: 10544019
• 负责人: Camilla Ferreira Wenceslau
• 金额: $ 37.25万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-15 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10544019
• 关键词: Actins; Adult; Advanced Development; Affect; Animal Model; Animals; Aorta; Arteries; Attention; Bacteria; Binding; Biological Markers; Blood Pressure; Blood Vessels; Cell Death; Cells; Characteristics; Chronic; Circulation; Data; Dependence; FPR1 gene; Female; Functional disorder; G-Protein-Coupled Receptors; Genetic Engineering; Germ-Free; Goals; Human; Hypertension; Immune; Immune system; Immunobiology; Inflammation; Infusion procedures; Innate Immune System; Interdisciplinary Study; Intrinsic factor; Knockout Mice; Lead; Leaky Gut; Leukocytes; Link; Lipopolysaccharides; Literature; Maintenance; Mediating; Mesentery; Mitochondria; Modeling; Molecular; Movement; Mus; National Heart, Lung, and Blood Institute; Patients; Pattern recognition receptor; Peptide Initiation Factors; Peptides; Play; Polymers; Rattus; Receptor Activation; Research; Research Personnel; Research Project Grants; Resistance; Role; Sentinel; Signal Pathway; Source; Technology; Testing; Therapeutic; Time; Tissues; Vascular Diseases; Vascular remodeling; antagonist; blood pressure elevation; blood pressure reduction; cell injury; cell motility; cofilin; driving force; fMet-Leu-Phe receptor; formyl peptide; high salt diet; hypertensive; innate immune function; innovation; juvenile animal; male; mature animal; microbiota; network dysfunction; neutrophil; normotensive; novel; novel therapeutic intervention; pathogen; polymerization; pressure; prevent; receptor; sensor; sex; vascular injury; zonulin

PROJECT SUMMARY WENCESLAU, CAMILLA F. One of the major pathophysiological characteristics of hypertension is the presence of vascular remodeling. Accordingly, it has been shown that 100% hypertensive subjects present small artery remodeling. However, there is a gap in the literature in understanding the exact trigger that leads to vascular remodeling, and this may limit our ability to adequately treat and prevent hypertension. Recent evidence implicates immune mechanisms in the pathophysiology of hypertension. Formyl peptide receptor (FPR)-1 is a pattern recognition receptor which plays a crucial role in the function of the innate immune system. In fact, one of the most powerful signaling pathways that induces actin polymerization and neutrophil movement is mediated by FPR-1. Recently, we observed that this receptor is expressed in arteries. Therefore, we questioned why a receptor that is crucial for immune defense and cell motility in leukocytes, would be expressed and functional in arteries? We observed that activation of FPR-1 in arteries is important for the temporal reorganization of actin, which rapidly induces actin polymerization. FPR-1 is a G-protein-coupled receptor that can bind N-formyl peptides produced by bacterial degradation. Interestingly, mitochondria carry hallmarks of their bacterial ancestry. Consequently, both mitochondrial and bacterial-derived peptides have a formyl group at their N-terminus. Therefore, N-formyl peptides (NFPs), regardless of origin, are recognized by FPR-1 as pathogens and thus play a role in the initiation of inflammation. Here, we observed for the first time that NFPs are present in the circulation of hypertensive animals and humans. Therefore, it is plausible to suggest that synergistic action of leaky gut-derived bacteria NFPs and cell damage-derived mitochondria NFPs lead to FPR-1 activation. Consequently, FPR-1 activation maybe the trigger to induce vascular remodeling, via actin polymerization, and subsequently, hypertension. This planned research is uniquely suited to the NHLBI Early Stage Investigator (ESI)-Research Project Grant (R01). It is innovative and has a strong, translational and multi-disciplinary research team of collaborators that have the capabilities and expertise to make this project successful. As an independent ESI, my short-term goal is to use state-of-art approaches, including culture-pressure myographs, genetic-engineering technologies, and arteries from humans and animals to explore a major driving force behind vascular-immune network dysfunction in hypertension.

Project摘要Wenceslau，Camilla F. 高血压的主要病理生理特征之一是存在血管 重塑。因此，已经表明100％高血压受试者表现出小动脉重塑。 但是，文献中存在差距，了解导致血管重塑的确切触发因素，并 这可能会限制我们充分治疗和预防高血压的能力。 最近的证据暗示了高血压病理生理学中的免疫机制。甲基肽 受体（FPR）-1是一种模式识别受体，在先天免疫的功能中起着至关重要的作用 系统。实际上，诱导肌动蛋白聚合和中性粒细胞的最强大的信号通路之一 运动由FPR-1介导。最近，我们观察到该受体在动脉中表达。所以， 我们质疑为什么对白细胞中免疫防御和细胞运动至关重要的受体将是 在动脉中表达并发挥作用？我们观察到，动脉中FPR-1的激活对于 肌动蛋白的时间重组，会迅速诱导肌动蛋白聚合。 FPR-1是一种G蛋白偶联受体，可以结合细菌产生的N-甲胺肽 降解。有趣的是，线粒体具有其细菌血统的标志。因此，两者 线粒体和细菌衍生的肽在其N末端具有甲基。因此，N-甲基胺 肽（NFP），无论起源如何，FPR-1都被认为是病原体，因此在开始中起作用 炎症。在这里，我们首次观察到NFP存在于高血压的循环中 动物和人类。因此，提出渗漏肠道细菌的协同作用是合理的 NFP和细胞损伤衍生的线粒体NFP会导致FPR-1激活。因此，FPR-1激活 也许是通过肌动蛋白聚合以及随后的高血压诱导血管重塑的触发因素。 这项计划的研究非常适合NHLBI早期研究员（ESI）研究项目 格兰特（R01）。它具有创新性，并拥有一个强大，翻译和多学科的合作研究团队 具有使该项目成功的能力和专业知识。作为独立的ESI，我的短期 目标是使用最先进的方法，包括文化压力仪，遗传工程技术， 和人类和动物的动脉探索血管免疫网络背后的主要动力 高血压功能障碍。