Neutrophil Chemotaxis in Autoinflammation

自身炎症中的中性粒细胞趋化性

• 批准号: 8541234
• 负责人: Anna Huttenlocher
• 金额: $ 32.01万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-15 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8541234
• 关键词: Address; Arthritis; Asthma; Autoimmunity; Biological Models; Biosensor; Cardiovascular Diseases; Cells; Chemotactic Factors; Chemotaxis; Chronic; Chronic Granulomatous Disease; Complex; Cues; Defect; Development; Disease; Disease model; Dissection; Equilibrium; Goals; Health; Heart Diseases; Homeostasis; Hydrogen Peroxide; IL8 gene; IL8RB gene; Image; Immigration; Immune; Immune response; Immune system; Immunologic Deficiency Syndromes; In Vitro; Inborn Genetic Diseases; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Knowledge; Leukocytes; Life; Malignant Neoplasms; Mediating; Molecular; Monomeric GTP-Binding Proteins; Mutate; NADP; NADPH Oxidase; Neutrophil Infiltration; Pathogenesis; Pathway interactions; Phosphoric Monoester Hydrolases; Play; Positioning Attribute; Process; Protein Tyrosine Phosphatase; Reactive Oxygen Species; Recurrence; Regulation; Reporting; Research; Resolution; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Sterility; Syndrome; System; Testing; Tissues; Transgenic Organisms; Work; Wound Healing; Zebrafish; cell motility; human CYBA protein; human disease; in vivo; innovation; intercellular communication; migration; neutrophil; novel; optogenetics; oxidation; public health relevance; src-Family Kinases; therapeutic target; tool; trafficking; wound

DESCRIPTION (provided by applicant): Autoinflammatory syndromes comprise a heterogeneous group of inherited disorders characterized by recurrent episodes of aseptic inflammation involving cells of the innate immune system. A hallmark of these disorders is the abnormal infiltration of neutrophils into tissues, suggesting that defects in neutrophil traffickin or motility may contribute to disease pathogenesis. Critical steps during the inflammatory response include leukocyte polarization and migration in the direction of chemoattractant. The long term goal of our work is to define signaling pathways that regulate neutrophil chemotaxis and to understand the implications of these mechanisms to the pathogenesis of chronic inflammatory disease by using zebrafish as a model system to examine neutrophil chemotaxis and inflammation in vivo. Knowledge of the basic mechanisms that regulate neutrophil chemotaxis should provide therapeutic targets for autoinflammatory syndromes and other disease states in which inflammation is central to pathogenesis, including heart disease, asthma, arthritis and inflammatory bowel disease. The strength of this proposal lies in the use of novel transgenic zebrafish lines that we have developed and the application of optogenetic tools to study neutrophil chemotaxis and inflammation in vivo. The hypothesis that guides this research is that neutrophil chemotaxis, mediated by the balance between reactive oxygen species (ROS), Src family kinases and tyrosine phosphatase signaling modulates the development and resolution of inflammation in vivo. We have made the following observations that support this proposal. 1. We recently discovered that hydrogen peroxide is an early signal that attracts neutrophils to wounds through the oxidation-mediated activation of the Src family kinase, Lyn. 2. We have developed optogenetic tools that allow the dissection of the molecular mechanisms that regulate neutrophil chemotaxis and bidirectional migration in vivo. 3. We were the first to report that neutrophils migrate away from wounds, in a process called "reverse migration" that may mediate local resolution of inflammation or may prime subsequent immune responses. 4. We have identified specific signaling molecules that mediate neutrophil reverse migration, including the tyrosine phosphatase SHP1 that has been associated with autoinflammation. We are now uniquely positioned to make rapid progress with the following Specific Aims: Aim 1. Elucidate how the Src family kinase, Lyn, regulates neutrophil chemotaxis and inflammation in zebrafish. Aim 2. Elucidate the role of reactive oxygen species (ROS) in the regulation of neutrophil motility and inflammation. Aim 3. Use zebrafish as a model system to study neutrophil chemotaxis in autoinflammation in vivo. The proposed work is innovative because of the application of live imaging and optogenetic tools to address fundamental questions about neutrophil motility during inflammation in zebrafish. The work is significant because of the potential to identify new strategies to control neutrophil-mediated inflammation in vivo, which plays a central role in the pathogenesis of many human diseases including cardiovascular disease, autoimmunity and cancer.

描述（由申请人提供）：自炎综合征包括一组异质的遗传性疾病，其特征是无菌炎症的复发发作，涉及先天免疫系统的细胞。这些疾病的标志是中性粒细胞异常浸润到组织中，这表明嗜中性粒细胞的缺陷或运动性可能导致疾病发病机理。炎症反应期间的关键步骤包括白细胞极化和朝向吸引力方向迁移。我们工作的长期目标是定义调节中性粒细胞趋化性的信号传导途径，并通过使用斑马鱼作为模型系统检查中性粒细胞趋化性和体内炎症，了解这些机制对慢性炎性疾病的发病机理的影响。了解调节中性粒细胞趋化性的基本机制应为自炎综合征和其他疾病状态提供治疗靶标，其中炎症是发病机理至关重要的，包括心脏病，哮喘，关节炎，关节炎和炎症性肠病。该提议的强度在于我们开发的新型转基因斑马鱼线以及在体内研究中性粒细胞趋化性和炎症的应用。指导这项研究的假设是，中性粒细胞趋化性是由活性氧（ROS），SRC家族激酶和酪氨酸磷酸酶信号传导之间的平衡介导的，可调节体内炎症的发育和分辨率。我们进行了以下观察，以支持该提案。 1。我们最近发现，过氧化氢是一种早期信号，它通过氧化介导的SRC家族激酶Lyn的氧化介导的激活吸引中性粒细胞。 2。我们开发了光遗传学工具，可以解剖分子机制，这些机制调节体内中性粒细胞趋化性和双向迁移。 3。我们是第一个报告中性粒细胞从伤口迁移的人，这是一个称为“反向迁移”的过程，该过程可能介导局部炎症的局部分辨率，或者可能促进随后的免疫反应。 4。我们已经确定了介导嗜中性粒细胞反向迁移的特定信号分子，包括与自炎有关的酪氨酸磷酸酶SHP1。现在，我们在以下特定目标方面取得了独特的位置：目标1。阐明SRC家族激酶如何调节斑马鱼中嗜中性粒细胞趋化性和炎症。目标2。阐明活性氧（ROS）在中性粒细胞运动和炎症调节中的作用。目标3。使用斑马鱼作为模型系统，研究体内自炎的中性粒细胞趋化性。提出的工作具有创新性，因为实时成像和光遗传学工具在斑马鱼炎症过程中使用了有关中性粒细胞运动的基本问题。这项工作很重要，因为有可能确定控制中性粒细胞介导的体内炎症的新策略，在体内炎症，这在许多人类疾病的发病机理中起着核心作用，包括心血管疾病，自身免疫和癌症。