Neutrophil lineage in inflammation

炎症中的中性粒细胞谱系

• 批准号: 10651774
• 负责人: Sergio Daniel Catz
• 金额: $ 246.46万
• 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/10651774
• 关键词: Address; Adult; Aorta; Apoptosis; Area; Arterial Fatty Streak; Atherosclerosis; Attenuated; Automobile Driving; Biology; Bone Marrow; Cardiovascular Diseases; Cause of Death; Cell Lineage; Cell physiology; Cells; Cellular biology; Cessation of life; Chronic; Circulation; Complex; Coronary Arteriosclerosis; Cues; Cytoplasmic Granules; Cytoprotection; Data; Development; Disease; Disease Progression; Endothelium; Evaluation; Exocytosis; Genetic; Goals; Granulopoiesis; Heart Diseases; Hematological Disease; Hematopoietic stem cells; Heterogeneity; Human; Hyperlipidemia; Immunology; Infection; Inflammasome; Inflammation; Inflammatory; Innate Immune Response; Interleukin-1 beta; Invaded; Laboratory Research; Lesion; Longevity; Mammals; Mediating; Mediator; Mission; Mitochondria; Modeling; Molecular; Mus; Myocardial Infarction; National Heart, Lung, and Blood Institute; Neutrophil Activation; Pathogenesis; Pathogenicity; Pathologic; Pathology; Plasma; Prevention; Process; Production; Proteins; Receptor Signaling; Regulation; Research Personnel; Research Project Grants; Role; Rupture; Signal Transduction; Technology; Testing; Tissues; Validation; adaptive immune response; atherogenesis; atherosclerotic plaque rupture; design; extracellular; human subject; interdisciplinary approach; microorganism; neutrophil; novel strategies; novel therapeutics; pre-clinical; progenitor; programs; response; secretory protein; trafficking; translational approach

ABSTRACT Neutrophils constitute the first line of cellular defense against pathogenic microorganisms. In response to pro- inflammatory cues, unrestricted neutrophil activation induces tissue damage. To avoid deleterious effects to the host, neutrophil numbers, activation, and lifespan must be tightly regulated, but the molecular mechanisms that control neutrophils in the context of inflammatory disease remain elusive. Cardiovascular disease is the leading global cause of death. Recent evidence supports an important role for neutrophils in the development of coronary artery disease (CAD). Neutrophils are present in early aortic lesions and in rupture-prone atherosclerotic plaques, and a positive correlation between plasma levels of neutrophil secretory proteins and CAD has been established, suggesting that neutrophil exocytosis mediates detrimental effects in CAD. Furthermore, neutrophil production is increased in the bone marrow in atherosclerotic models and newly identified neutrophil precursors are now known to mediate inflammation. How neutrophil subsets contribute to disease progression in CAD has not been studied and the regulation of neutrophil diversity in disease is unknown. The inflammasome is an emerging driver in atherosclerosis; however, the role of the NLRP3 inflammasome activation selectively in neutrophils on atherogenesis has not been studied and the mechanisms regulating the functions of neutrophil lineage cells in the context of inflammasome activation and atherogenesis remain unknown. In this synergistic program, Project 1 Neutrophil Development During Inflammation and Atherosclerosis will study how neutrophil heterogeneity is modulated in human subjects with CAD, and how the NLRP3 inflammasome in neutrophil progenitors influences granulopoiesis and neutrophil heterogeneity in atherosclerosis. Project 2 Neutrophil Mechanisms During Inflammation and Atherosclerosis will test the hypothesis that hyperlipidemia differentially regulates vesicular trafficking and associated functions of neutrophil precursors in CAD, establish mechanisms of NLRP3-induced neutrophil exocytosis dysregulation and implement translational approaches to decrease neutrophil inflammation in CAD. Project 3 Neutrophil Survival and Demise During Inflammatory States will characterize the expression and function of components of the NLRP3 inflammasome in cells of the neutrophil lineage, and will define the effects of hyperlipidemia-induced inflammation and the roles of death receptor signaling in IL-1β production, mitochondrial apoptosis in viability of neutrophil lineage cells, and necroptosis signaling in atherogenesis. Our synergistic and unique program uses the complementary expertise of three renown researchers, experts in the areas of neutrophil development, neutrophil intracellular function regulation and inflammation, to study the central hypothesis that unrestricted activation of neutrophil progenitors and mature neutrophils is a fundamental process in cardiovascular disease. These studies will lead to novel approaches to treat neutrophil-mediated inflammation in CAD.

抽象的 中性粒细胞构成了针对致病微生物的细胞防御的第一线。回应亲 炎症提示，无限制的中性粒细胞激活会诱导组织损伤。避免对 宿主，中性粒细胞数，激活和寿命必须严格调节，但分子机制必须 在炎症性疾病背景下的中性粒细胞仍然难以捉摸。心血管疾病是领先的 全球死亡原因。最近的证据支持中性粒细胞在冠状动脉发展中的重要作用 动脉疾病（CAD）。嗜中性粒细胞存在于早期主动脉病变中，在易发性动脉粥样硬化中存在 斑块和血浆中性粒细胞分泌蛋白和CAD之间的正相关已是 建立，表明嗜中性粒细胞增多症介导了CAD中的有害作用。此外，中性粒细胞 动脉粥样硬化模型中的骨髓中的产生和新鉴定的中性粒细胞前体的产生增加 现在媒体发炎已知。中性粒细胞子集如何促进CAD的疾病进展 没有研究，疾病中嗜中性粒细胞多样性的调节尚不清楚。炎症是一个 动脉粥样硬化的新兴驱动器；但是，NLRP3炎性体激活的作用选择性地在 嗜中性粒细胞在动脉粥样硬化上尚未进行研究，并且调节中性粒细胞功能的机制 在炎性体激活和动脉粥样硬化的背景下，谱系细胞尚不清楚。在这种协同作用中 计划，项目1炎症和动脉粥样硬化期间的中性粒细胞发育将研究中性粒细胞 异质性是在人类受试者中调节的，以及中性粒细胞中的NLRP3炎症 祖细胞影响动脉粥样硬化中的颗粒和中性粒细胞异质性。项目2中性粒细胞 炎症和动脉粥样硬化期间的机制将检验高脂血症差异化的假设 调节囊泡运输和中性粒细胞前体的相关功能，建立机制 NLRP3诱导的中性粒细胞胞吐作用失调并实施转化方法以减少 CAD中的中性粒细胞注射。炎症状态下的3个中性粒细胞生存和灭亡将 表征中性粒细胞细胞中NLRP3炎症体组件的表达和功能 谱系，并将定义高脂血症诱导的注射和死亡接收器的作用 IL-1β产生的信号传导，中性粒细胞细胞生存力的线粒体凋亡和坏死性的信号传导 动脉粥样硬化中的信号传导。我们的协同和独特的计划使用三个完善专业知识 著名的研究人员，中性粒细胞发育领域的专家，中性粒细胞内功能调节 和炎症，研究中心假设，即中性粒细胞祖细胞和成熟的激活 中性粒细胞是心血管疾病的基本过程。这些研究将导致新颖的方法 治疗CAD中嗜中性粒细胞介导的炎症。