Neutrophil Mechanisms During Inflammation and Atherosclerosis

炎症和动脉粥样硬化期间的中性粒细胞机制

• 批准号: 10270898
• 负责人: Sergio Daniel Catz
• 金额: $ 62.25万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-16 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10270898
• 关键词: Actins; Affect; Apolipoprotein E; Atherosclerosis; Autoimmunity; Autophagocytosis; Azurophilic Granule; Biology; Bone Marrow; Cardiovascular Diseases; Cell physiology; Cellular biology; Chronic; Collaborations; Coronary Arteriosclerosis; Cytoplasmic Granules; Defect; Development; Dimensions; Disease; Dyslipidemias; Exocytosis; Exposure to; Family; Fibrosis; Genetic; High Fat Diet; Human; Hyperlipidemia; In Vitro; Inflammasome; Inflammation; Inflammatory; Innate Immune Response; Knock-in; Lead; Mass Spectrum Analysis; Mediating; Mediator of activation protein; Methods; Microscopy; Modeling; Molecular; Monomeric GTP-Binding Proteins; Morphology; Mus; NADPH Oxidase; Neutrophil Activation; Organelles; Pathway interactions; Patients; Physiology; Process; Production; Proteomics; Reactive Oxygen Species; Regulation; Reperfusion Injury; Research; Resolution; Role; Sepsis; Specificity; Systemic Inflammatory Response Syndrome; Testing; autoinflammatory; endothelial dysfunction; exosome; extracellular; in vivo; inhibitor/antagonist; marenostrin; mouse model; nanometer; neutrophil; novel; progenitor; rab GTP-Binding Proteins; secretory protein; spatiotemporal; systemic inflammatory response; trafficking; translational approach; translational study; treatment strategy; vesicle transport; western diet

Project Summary/Abstract Intracellular vesicular transport is essential for all aspects of neutrophil physiology and defects in this mechanism leads to disease in humans. Uncontrolled neutrophil activation and neutrophil secretory proteins are associated with the development of systemic inflammation, endothelial dysfunction, coronary artery disease (CAD) and autoinflammatory disease. We found that the recently identified neutrophil progenitors (NePs) and immature neutrophils contain morphologically and functionally unique secretory organelles. We also show that both the inflammasome and exposure to high-fat diets (HFD) differentially regulate neutrophil activation and this is affected by their maturation state. We have identified several key regulatory factors essential for the control of neutrophil granule trafficking in vitro and in vivo, including the small GTPase Rab27a, its effectors JFC1 and Munc13-4, and NeP-specific effectors. The control of specific vesicular trafficking pathways in neutrophil precursors constitutes a unique approach to reduce inflammatory disorders highlighting the need for treatments targeting these pathways. In this application, we will use genetically modified mouse models and human neutrophils, to test the hypothesis that molecular mechanisms of vesicular trafficking and neutrophil functions differentially modulate neutrophils- and NePs-mediated inflammation in CAD. We will study neutrophil functions in hyperlipidemia in CAD (collaboration with Project 1) and inflammasome-mediated mechanisms (collaboration with Project 3). We will use novel inhibitors of neutrophil secretion in translational approaches to reduce inflammation. The significance of the proposed research is that elucidating the mechanisms regulating vesicular trafficking and secretion in neutrophils and NePs will lead to effective strategies for the treatment of systemic inflammation in CAD. To test our hypotheses we propose the following Specific Aims: 1) Test the hypothesis that hyperlipidemia differentially regulates vesicular trafficking and associated functions in neutrophils and precursors in CAD; 2) Elucidate the mechanisms of azurophilic granule exocytosis dysregulation induced by inflammasome activation in mature neutrophils and their precursors; 3) Mechanistic and translational studies of neutrophil- mediated inflammation in CAD. The proposed research should uncover the molecular mechanisms regulating vesicular transport in neutrophil precursors and lead to effective new strategies to treat inflammation in CAD.

项目概要/摘要 细胞内囊泡运输对于中性粒细胞生理学的各个方面都至关重要，并且该机制存在缺陷 导致人类疾病。不受控制的中性粒细胞活化和中性粒细胞分泌蛋白相关 随着全身炎症、内皮功能障碍、冠状动脉疾病（CAD）和 自身炎症性疾病。我们发现最近发现的中性粒细胞祖细胞（NePs）和未成熟的 中性粒细胞含有形态和功能独特的分泌细胞器。我们还表明，两者 炎症小体和高脂肪饮食（HFD）对中性粒细胞活化有不同的调节作用，这是 受其成熟状态的影响。我们已经确定了几个对于控制 中性粒细胞颗粒体外和体内运输，包括小 GTPase Rab27a、其效应器 JFC1 和 Munc13-4 和 NeP 特异性效应子。中性粒细胞中特定囊泡运输途径的控制 前体构成了减少炎症性疾病的独特方法，凸显了治疗的必要性 针对这些途径。在此应用中，我们将使用转基因小鼠模型和人类 中性粒细胞，检验囊泡运输和中性粒细胞功能的分子机制的假设 差异调节 CAD 中中性粒细胞和 NePs 介导的炎症。我们将研究中性粒细胞功能 CAD 中的高脂血症（与项目 1 合作）和炎症小体介导的机制（合作 与项目 3）。我们将在转化方法中使用新型中性粒细胞分泌抑制剂来减少 炎。该研究的意义在于阐明了囊泡的调节机制 中性粒细胞和 NeP 的运输和分泌将导致治疗系统性贫血的有效策略 CAD 中的炎症。为了检验我们的假设，我们提出以下具体目标： 1) 检验假设 高脂血症差异调节中性粒细胞和前体细胞中的囊泡运输和相关功能 在 CAD 中； 2）阐明炎症小体诱导的嗜天青颗粒胞吐失调的机制 成熟中性粒细胞及其前体的激活； 3) 中性粒细胞的机制和转化研究 CAD 中介导的炎症。拟议的研究应该揭示调节的分子机制 中性粒细胞前体中的囊泡运输，并导致治疗 CAD 炎​​症的有效新策略。