Regulation of inflammatory cell migration in asthma

哮喘炎症细胞迁移的调节

基本信息

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
项目类别：
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

项目摘要

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）：控制细胞表面的氧化还原环境可调节关键细胞功能，包括细胞 - 细胞识别，细胞粘附和细胞迁移。我们发现，半乳糖素-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细胞表面上的硫糖酶蛋白二硫化物异构酶（PDI）结合，并保留在细胞表面上的酶，在此酶在其中酶修饰细胞表面蛋白，以增加这些蛋白质上还原硫醇的数量。已经提出了细胞表面PDI来调节其他类型的白细胞（例如血小板）的迁移，通过修饰整合素，将Galectin-9结合牵涉到通过细胞外基质来调节整合素介导的T细胞迁移的新机制。该提案的目标是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）确定Galectin-9在使用鼠模型的Murine模型中，确定Galectin-9在Th2细胞和嗜酸性粒细胞中浸润到炎症组织中的作用。由于Galectin-9由炎性细胞（例如肥大细胞，树突状细胞和嗜酸性粒细胞）以及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中的主要效应细胞，我们将确定galectin-9在Astha asthma模型中的作用。因此，在AIM1中，我们将确定所有T细胞和嗜酸性粒细胞糖蛋白受体，这些受体通过亲和色谱和质谱法结合了乳糖素9。我们将确定负责Galectin-9结合的聚糖配体。我们将研究Galectin-9与受体结合的机制增强迁移，检查细胞表面上的受体迁移率，受体构象和下游基因表达。在AIM 2中，我们将比较Galectin-9和Galectin-1 NULL小鼠，以响应气道炎症以及产生的一系列效应细胞和细胞因子。我们将确定外源施用的Galectin-9对气道炎症程度和各种效应细胞募集的影响。我们将通过检查lectectin-9嵌合小鼠中的气道炎症来确定白细胞衍生的与组织衍生的组织的功能。研究哮喘中白细胞迁移的这种新机制将确定新的潜在治疗方法，以改善哮喘中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非常新颖，哮喘模型是我们组的全新研究领域。该项目是高风险，但潜在的产量很高，因此适合R21应用。公共卫生相关性：与人类健康的相关性：哮喘需要新的疗法，这种疾病影响了约10％的美国儿童和成人。由于这种毁灭性疾病发生的慢性炎症，哮喘患者的肺部造成永久性组织损伤。通过阻止炎症细胞进入并通过组织迁移的能力来防止哮喘的炎症，这是设计新治疗方法的关键目标。我们的建议研究了哮喘肺中产生的分子的先前未知的作用，我们发现促进了炎症细胞的迁移。了解该分子如何触发细胞迁移将允许开发新方法，以防止哮喘患者的肺部炎症和随后的组织损害。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
通讯作者：
Baum,LindaG