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: 10651790
• 负责人: Sergio Daniel Catz
• 金额: $ 58.73万
• 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/10651790
• 关键词: Actins; Affect; Apolipoprotein E; Atherosclerosis; Autoimmune Diseases; 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; Mass Spectrum Analysis; Mediating; Mediator; Methods; 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; Role; Sepsis; Specificity; Systemic Inflammatory Response Syndrome; Testing; autoinflammatory diseases; endothelial dysfunction; exosome; extracellular; in vivo; inhibitor; marenostrin; mouse model; nanometer; neutrophil; novel; progenitor; rab GTP-Binding Proteins; secretory protein; spatiotemporal; superresolution microscopy; systemic inflammatory response; trafficking; translational approach; translational study; treatment strategy; ultra high resolution; 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.

项目摘要/摘要 细胞内囊泡转运对于中性粒细胞生理的各个方面至关重要 导致人类疾病。不受控制的中性粒细胞激活和中性粒细胞分泌蛋白是相关的 随着系统性炎症，内皮功能障碍，冠状动脉疾病（CAD）和 自发疾病。我们发现最近确定的中性粒细胞祖细胞（NEP）和未成熟 中性粒细胞包含形态和功能独特的分泌细胞器。我们还表明了这两个 炎症体和暴露于高脂饮食（HFD）差异调节中性粒细胞激活，这是 受其成熟状态的影响。我们已经确定了控制控制的几个关键调节因素 中性粒细胞颗粒在体外和体内运输，包括小GTPase Rab27a，其效应子JFC1和 MUNC13-4和NEP特异性效应子。控制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，突出了治疗的需求 针对这些途径。在此应用中，我们将使用转基因的鼠标模型和人类 中性粒细胞，以检验以下假设：囊泡运输和中性粒细胞功能的分子机制 差异调节CAD中的嗜中性粒细胞和NEP介导的炎症。我们将研究中性粒细胞功能 CAD中高脂血症（与项目1合作）和炎症体介导的机制（协作 与项目3）。我们将在翻译方法中使用中性粒细胞分泌的新型抑制剂来减少 炎。拟议的研究的意义在于阐明调节囊泡的机制 中性粒细胞和NEP中的贩运和分泌将导致有效治疗全身的策略 CAD中的炎症。为了检验我们的假设，我们提出以下特定目的：1）检验以下假设。 高脂血症差异地调节了囊泡运输和中性粒细胞和前体的相关功能 在CAD中； 2）阐明炎性体诱导的硫醇颗粒胞吐作用失调的机制 成熟中性粒细胞及其前体的激活； 3）中性粒细胞的机械和翻译研究 CAD中介导的炎症。拟议的研究应揭示调节的分子机制 中性粒细胞前体中的囊泡转运，并导致有效治疗CAD炎症的新策略。