Neutrophil Mechanisms During Inflammation and Atherosclerosis

项目摘要/摘要 胞内囊泡转运是中性粒细胞生理各方面所必需的，也是这一机制中的缺陷。 会导致人类患病。中性粒细胞激活失控与中性粒细胞分泌蛋白相关 随着全身炎症、内皮功能障碍、冠心病(CAD)和 自身炎症性疾病。我们发现最近发现的中性粒细胞前体细胞(NEP)和幼稚粒细胞 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， 炎症体和暴露于高脂饮食(HFD)不同地调节中性粒细胞的激活，这是 受其成熟状态的影响。我们已经确定了几个关键的监管因素，这对控制 中性粒细胞在体外和体内的转运，包括小GTP酶Rab27a、其效应因子JFC1和 Munc13-4和NEP特定效应器。中性粒细胞特定囊泡转运途径的调控 前体是减少炎症性疾病的独特方法，突出了治疗的必要性 瞄准这些小路。在这项应用中，我们将使用转基因小鼠模型和人类 中性粒细胞，以检验囊泡转运和中性粒细胞功能的分子机制 中性粒细胞和中性粒细胞介导的炎症在冠心病中的差异调节。我们将研究中性粒细胞的功能 冠心病中的高脂血症(与项目1合作)和炎症体介导的机制(合作 项目3)。我们将在翻译方法中使用新型的中性粒细胞分泌抑制剂来减少 发炎。这项研究的意义在于阐明了水泡的调节机制。 中性粒细胞和非中性粒细胞的运输和分泌将导致系统性红斑狼疮的有效治疗策略。 冠心病的炎症反应。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 高脂血症对中性粒细胞和前体细胞的囊泡转运及其相关功能的不同调节 2)阐明炎性小体引起嗜天青颗粒胞吐功能失调的机制 成熟的中性粒细胞及其前体细胞的激活；3)中性粒细胞的机制和翻译研究- 在冠心病中介导炎症反应。这项拟议中的研究应该揭示调控的分子机制 中性粒细胞前体中的囊泡运输，并导致有效的新策略来治疗冠心病的炎症。

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.