Regulation of inflammatory cell migration in asthma

哮喘炎症细胞迁移的调节

• 批准号: 8063630
• 负责人: Linda G Baum
• 金额: $ 19.25万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8063630
• 关键词: Adhesions; Adoptive Transfer; Adult; Affect; Affinity Chromatography; Allergens; American; Apoptosis; Area; Asthma; Automobile Driving; Binding; Blood Platelets; Cell Surface Proteins; Cell Surface Receptors; Cell membrane; Cell physiology; Cell surface; Cell-Cell Adhesion; Cells; Child; Chronic; Dendritic Cells; Development; Disease; Effector Cell; Endothelial Cells; Environment; Enzymes; Epithelial Cells; Extracellular Matrix; Family; Galactose Binding Lectin; Galectin 1; Gene Expression; Glycoproteins; Goals; Health; Hematopoietic; Human; Immigration; Immune response; In Vitro; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Integrins; Interferons; Investigation; Knockout Mice; Laboratories; Leukocytes; Ligands; Lung; Lung Inflammation; Lymphocyte; Mass Spectrum Analysis; Mediating; Modeling; Modification; Molecular Conformation; Morbidity - disease rate; Mus; Oxidation-Reduction; Pathogenesis; Patients; Phenotype; Polysaccharides; Population; Prevalence; Process; Production; Protein Disulfide Isomerase; Proteins; Regulation; Research; Role; Signal Transduction; Stimulus; Structure of parenchyma of lung; Sulfhydryl Compounds; Surface; T-Lymphocyte; Th1 Cells; Th2 Cells; Therapeutic; Tissues; airway inflammation; allergic airway disease; carbohydrate binding protein; cell motility; chemokine; cytokine; design; eosinophil; high risk; improved; in vivo; in vivo Model; innovation; macrophage; mast cell; member; migration; mortality; novel; novel strategies; novel therapeutic intervention; pathogen; prevent; public health relevance; receptor; receptor binding; research study

DESCRIPTION (provided by applicant): Control of the redox environment at the cell surface regulates critical cellular functions, including cell-cell recognition, cell adhesion and cell migration. We have found that galectin-9 regulates migration of specific types of leukocytes, Th2 cells and eosinophils, through extracellular matrix. Galectin-9 binds to the thioreductase Protein Disulfide Isomerase (PDI) on surface of T cells and retains the enzyme on the cell surface, where the enzyme modifies cell surface proteins to increase the number of reduced thiols on these proteins. Cell surface PDI has been proposed to regulate migration of other types of leukocytes, such as platelets, through modification of integrins, implicating galectin-9 binding as a novel mechanism for regulating integrin-mediated T cell migration through extracellular matrix. The goals of this proposal are 1) to elucidate the mechanism by which galectin-9 regulates Th2 cell and eosinophil migration through extracellular matrix, and 2) to determine the role of galectin-9 in infiltration of Th2 cells and eosinophils into inflamed tissue in vivo, using a murine model of asthma. As galectin-9 is expressed by inflammatory cells, such as mast cells, dendritic cells, and eosinophils, as well as by endothelial cells and bronchial epithelial cells, and as Th2 cells and eosinophils are primary effector cells in asthma, we will determine the role of galectin-9 in an asthma model in vivo. Thus, in Aim1, we will identify all T cell and eosinophil glycoprotein receptors that bind galectin-9 by affinity chromatography and mass spectrometry. We will identify glycan ligands responsible for galectin-9 binding. We will investigate mechanisms by which galectin-9 binding to receptors enhances migration, examining receptor mobility on the cell surface, receptor conformation, and downstream gene expression. In Aim 2, we will compare galectin-9 and galectin-1 null mice for responsiveness to inducers of airway inflammation and the array of effector cells and cytokines produced. We will determine the effect of exogenously administered galectin-9 on the extent of airway inflammation and recruitment of various effector cells. We will determine the function of leukocyte derived vs. tissue derived galectin-9 by examining airway inflammation in galectin-9 chimeric mice. Investigation of this new mechanism of leukocyte migration in asthma will identify new potential therapeutic approaches to ameliorating the lung inflammation and tissue damage in asthma. The hypothesis that galectin-9 regulates leukocyte function by regulating the cell surface redox environment is very novel, and asthma models are an entirely new area of research for our group. This project is high- risk but potentially very high yield, and thus appropriate for an R21 application. PUBLIC HEALTH RELEVANCE: Relevance to human health: Novel therapies are needed for asthma, a disease that affects approximately 10% of American children and adults. Asthma patients develop permanent tissue damage in their lungs, due to the chronic inflammation that occurs in this devastating disease. Preventing the inflammation in asthma, by blocking the ability of inflammatory cells to enter into and migrate through tissue, is a critical goal in the design of new therapeutic approaches. Our proposal investigates a previously unknown effect of a molecule produced in asthmatic lung that we have found promotes the migration of inflammatory cells. Understanding how this molecule triggers cell migration will allow development of new approaches to prevent the inflammation and subsequent tissue damage seen in the lungs of asthma patients.

描述(由申请人提供)：细胞表面氧化还原环境的控制调节细胞的关键功能，包括细胞-细胞识别、细胞黏附和细胞迁移。我们发现Galectin-9通过细胞外基质调节特定类型的白细胞，Th2细胞和嗜酸性粒细胞的迁移。Galectin-9与T细胞表面的硫代还原酶蛋白二硫键异构酶(PDI)结合，并将该酶保留在细胞表面，该酶修饰细胞表面蛋白以增加这些蛋白上的还原型硫醇的数量。细胞表面PDI被认为可以通过整合素的修饰来调节其他类型白细胞的迁移，这意味着Galectin-9结合是调节整合素介导的T细胞通过细胞外基质迁移的一种新机制。这项建议的目的是1)阐明Galectin-9通过细胞外基质调节Th2细胞和嗜酸性粒细胞迁移的机制，以及2)利用哮喘小鼠模型，确定Galectin-9在Th2细胞和嗜酸性粒细胞在体内炎症组织中的渗透中的作用。由于Galectin-9由炎症细胞表达，如肥大细胞、树突状细胞和嗜酸性粒细胞，也有内皮细胞和支气管上皮细胞表达，而Th2细胞和嗜酸性粒细胞是哮喘的主要效应细胞，我们将在体内确定Galectin-9在哮喘模型中的作用。因此，在Aim1中，我们将通过亲和层析和质谱法鉴定所有与Galectin-9结合的T细胞和嗜酸性粒细胞糖蛋白受体。我们将确定与Galectin-9结合的葡聚糖配体。我们将研究Galectin-9与受体结合促进迁移的机制，检测细胞表面的受体迁移率、受体构象和下游基因表达。在目标2中，我们将比较Galectin-9和Galectin-1基因缺失小鼠对呼吸道炎症诱导剂的反应性，以及产生的效应细胞和细胞因子的阵列。我们将确定外源性给予Galectin-9对呼吸道炎症程度和各种效应细胞募集的影响。我们将通过检测Galectin-9嵌合小鼠的呼吸道炎症来确定白细胞来源的Galectin-9与组织来源的Galectin-9的功能。对哮喘中白细胞迁移这一新机制的研究将确定新的潜在治疗方法，以改善哮喘的肺部炎症和组织损伤。Galectin-9通过调节细胞表面氧化还原环境来调节白细胞功能的假设是非常新颖的，哮喘模型对我们团队来说是一个全新的研究领域。这个项目风险很高，但潜在的收益非常高，因此适合R21的应用。 公共卫生相关性：与人类健康相关：哮喘是一种影响大约10%美国儿童和成人的疾病，需要新的治疗方法。哮喘患者的肺部会出现永久性的组织损伤，这是因为这种毁灭性的疾病会导致慢性炎症。通过阻断炎症细胞进入组织并通过组织迁移的能力来预防哮喘的炎症，是设计新的治疗方法的关键目标。我们的提案调查了哮喘肺中产生的一种以前未知的分子的作用，我们发现这种分子促进了炎症细胞的迁移。了解这种分子是如何触发细胞迁移的，将有助于开发新的方法来预防哮喘患者肺部出现的炎症和随后的组织损伤。

项目成果

The road less traveled: regulation of leukocyte migration across vascular and lymphatic endothelium by galectins.

• DOI: 10.1007/s10875-010-9460-z
• 发表时间: 2011-02
• 期刊: JOURNAL OF CLINICAL IMMUNOLOGY
• 影响因子: 9.1
• 作者: Thiemann, Sandra;Baum, Linda G.
• 通讯作者: Baum, Linda G.

Burn control, an adipocyte-specific function for galectin-12.

烧伤控制，半乳糖凝集素 12 的脂肪细胞特异性功能。

• DOI: 10.1073/pnas.1115738108
• 发表时间: 2011
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Baum,LindaG