Neutrophil Mechanisms During Inflammation and Atherosclerosis

项目总结/摘要 胞内囊泡运输是必不可少的所有方面的中性粒细胞生理和缺陷，这一机制 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 自身炎性疾病我们发现，最近鉴定的中性粒细胞祖细胞（NePs）和未成熟的 嗜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， 炎性小体和暴露于高脂饮食（HFD）差异调节中性粒细胞活化，这是 受其成熟状态的影响。我们已经确定了几个关键的调控因素， 中性粒细胞颗粒在体外和体内的运输，包括小的GTTRab 27 a，其效应物JFC 1和 Munc 13 -4和NeP特异性效应子。中性粒细胞特异性囊泡运输途径的调控 前体构成了一种独特的方法，以减少炎症性疾病，突出了治疗的需要 针对这些路径。在这个应用中，我们将使用转基因小鼠模型和人类模型。 中性粒细胞，以检验假设，即囊泡运输和中性粒细胞功能的分子机制 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高脂血症（与项目1合作）和炎性小体介导的机制（合作 项目3）。我们将在翻译方法中使用新型中性粒细胞分泌抑制剂， 炎症本研究的意义在于阐明了细胞内小泡细胞的调控机制， 中性粒细胞和NePs的运输和分泌将导致治疗系统性 CAD炎症为了检验我们的假设，我们提出了以下具体目标：1）检验假设， 高脂血症差异调节中性粒细胞和前体细胞的囊泡运输和相关功能 2）阐明炎性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细胞的活化; 3）中性粒细胞活化的机制和翻译研究。 介导的炎症。拟议的研究应该揭示调节的分子机制 囊泡运输的中性粒细胞前体，并导致有效的新策略，以治疗炎症的CAD。

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.