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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：
7911394
负责人：
Linda G Baum
金额：
$ 23.1万
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/7911394
关键词：
Adhesions Adoptive Transfer Adult Affect Affinity Chromatography Allergens American Apoptosis Area Asthma Automobile Driving Binding Blood Platelets Cell Adhesion Cell Surface Proteins Cell Surface Receptors Cell membrane Cell physiology Cell surface 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调节关键的细胞功能，包括细胞-细胞识别、细胞粘附和细胞迁移。我们已经发现半乳糖凝集素-9调节特定类型的白细胞、Th 2细胞和嗜酸性粒细胞通过细胞外基质的迁移。半乳糖凝集素-9与T细胞表面上的硫还原酶蛋白二硫化物异构酶（PDI）结合，并将酶保留在细胞表面上，其中酶修饰细胞表面蛋白以增加这些蛋白上还原巯基的数量。已经提出细胞表面PDI通过整联蛋白的修饰来调节其他类型的白细胞（如血小板）的迁移，这暗示半乳糖凝集素-9结合是调节整联蛋白介导的T细胞通过细胞外基质迁移的新机制。该提议的目标是1）阐明半乳糖凝集素-9调节Th 2细胞和嗜酸性粒细胞通过细胞外基质迁移的机制，和2）使用哮喘的鼠模型确定半乳糖凝集素-9在Th 2细胞和嗜酸性粒细胞向体内发炎组织中的浸润中的作用。由于半乳糖凝集素-9由炎性细胞如肥大细胞、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，并且由于Th 2细胞和嗜酸性粒细胞是哮喘中的主要效应细胞，因此我们将确定半乳糖凝集素-9在体内哮喘模型中的作用。因此，在目标1，我们将确定所有的T细胞和嗜酸性粒细胞糖蛋白受体结合半乳糖凝集素-9的亲和层析和质谱。我们将鉴定负责半乳糖凝集素-9结合的聚糖配体。我们将研究半乳糖凝集素-9结合受体增强迁移的机制，检查细胞表面受体的迁移率，受体构象和下游基因表达。在目标2中，我们将比较半乳糖凝集素-9和半乳糖凝集素-1缺失小鼠对气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半乳糖凝集素-9对气道炎症程度和各种效应细胞募集的影响。我们将通过检查半乳糖凝集素-9嵌合小鼠中的气道炎症来确定白细胞来源的半乳糖凝集素-9与组织来源的半乳糖凝集素-9的功能。对哮喘中白细胞迁移的新机制的研究将为改善哮喘的肺部炎症和组织损伤提供新的潜在治疗方法。半乳糖凝集素-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，哮喘模型对我们小组来说是一个全新的研究领域。这个项目是高风险的，但潜在的收益非常高，因此适合于R21应用。公共卫生相关性：与人类健康的相关性：哮喘是一种影响大约10%的美国儿童和成人的疾病，需要新的治疗方法。哮喘患者在他们的肺部发展永久性组织损伤，由于慢性炎症，发生在这种毁灭性的疾病。通过阻断炎性细胞进入和迁移通过组织的能力来预防哮喘中的炎症，是设计新治疗方法的关键目标。我们的建议调查了一个以前未知的影响，分子产生的哮喘肺，我们已经发现，促进炎症细胞的迁移。了解这种分子如何触发细胞迁移将有助于开发新的方法来预防哮喘患者肺部的炎症和随后的组织损伤。