Cell Movement Through a TH2-Conditioned Extracellular Matrix

细胞通过 TH2 调节的细胞外基质运动

• 批准号: 9249663
• 负责人: NIZAR N JARJOUR
• 金额: $ 45.55万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9249663
• 关键词: Abbreviations; Acute; Adhesions; Adhesives; Affect; Alternative Splicing; Antibodies; Area; Asthma; Behavior; Benign; Binding Sites; Biological; Biology; Biopsy; Blocking Antibodies; Blood Platelets; Bronchoalveolar Lavage; Cell Surface Receptors; Cells; Characteristics; Chronic; Connective Tissue; Data; Deposition; Development; Employee Strikes; Endothelial Cells; Environment; Eotaxin; Epithelial Cells; Extracellular Matrix; Extracellular Matrix Proteins; Extrinsic asthma; Fibroblasts; Glutamic Acid; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Homologous Gene; Human; ITGAM gene; ITGB2 gene; Immobilization; In Vitro; Inflammation; Inflammatory; Integrins; Interleukin-3; Interleukin-5; Knowledge; Learning; Left; Leukocytes; Ligands; Lung; Lung Inflammation; Lung diseases; Maps; Mediating; Mediator of activation protein; Modeling; Movement; Mus; Outcome; Patients; Principal Investigator; Process; Proteins; Reagent; Regulation; Research; Role; Sampling; Site; Specificity; Staining method; Stains; Structure-Activity Relationship; Th2 Cells; The Sun; Vascular Cell Adhesion Molecule-1; Vitamin K; airway inflammation; airway remodeling; antigen challenge; asthmatic; asthmatic airway; base; carboxylate; carboxylation; cell motility; cytokine; density; eosinophil; eosinophilic inflammation; experimental study; insight; migration; novel; periostin; receptor; response; surface coating; trafficking; tumor

Our long-term goal is to understand how eosinophils (EOS) traffic to and interact in the ainway and contribute to the progression of asthma. aM32 integrin (CD11b/CD18) is highly activated on EOS obtained by bronchoalveolar lavage after segmental antigen challenge, suggesting that aM(32 functions becomes important as EOS extravasate to and migrate in the lung. However, little is known about roles of aMp2 and relevant ligand(s) in adhesion, migration, and activities of EOS in the airway. The overall objective of this proposal is to determine the role of aMp2 in modulating behavior of EOS in the ainway. Based on our preliminary data and current understanding of EOS biology and the extracellular matrix (ECM) in asthma, the current hypothesis is that periostin, an ECM protein characteristic of inflammation driven by T helper type 2 cells and found in the asthmatic ain/vay, is a dominant adhesive ligand for EOS aMp2 integrin and that the aMp2-periostin interaction is an important determinant of EOS function. Aim 1 is to define roles of aMp2, periostin and TGF-P-induced protein (TGFBI), a periostin homolog also found in lung, in adhesion, migration, sun/ival, and other functions of EOS activated by IL-3, IL-5, GM-CSF, or other activators. Aim 2 is to determine the structure-function relationship ofthe recognition of periostin by aMP2, map the aMp2-binding site(s), and define minimal constructs that when immobilized support, and when soluble block, EOS adhesion and migration. How the vitamin K-dependent y-carboxylation and alternative splicing affect periostin's biological activities will also be determined. Aim 3 is to understand the mechanism and significance ofthe striking increase of periostin that is found in the asthmatic airway. Periostin secretion from fibroblasts and epithelial cells stimulated by TGF-p or other factors, as well as its deposition into ECM and turnover will be analyzed. Antibodies to the various forms of periostin and TGFBI will be developed for localization in bronchial biopsies after segmental antigen challenge. Achieving the goals of this proposal will provide novel knowledge and a better understanding of EOS trafficking and functions and the interplay between EOS and the ECM in Th2-driven inflammation, and will generate agents and reagents that will allow this interplay to be studied and modulated. RELE^VANCE (See instructions): The proposed research will determine how the connective tissue protein periostin, which is strongly up- regulated in asthma, interacts with its cell-surface receptor protein aMP2 integrin (CD11b/CD18) on activated EOS, and supports attachment and migration of EOS. The project will provide new insights into the movement of EOS in the asthmatic ainway and the biology of connective tissue in the diseased lung.

我们的长期目标是了解嗜酸性粒细胞 (EOS) 如何在通道中流动和相互作用并做出贡献 到哮喘的进展。 aM32 整合素 (CD11b/CD18) 在 EOS 上被高度激活 分段抗原激发后支气管肺泡灌洗，表明 aM(32 功能变为 重要的是，EOS 会渗出并迁移到肺部。然而，人们对 aMp2 和 aMp2 的作用知之甚少。 气道中 EOS 粘附、迁移和活性的相关配体。本次活动的总体目标 提案的目的是确定 aMp2 在调节 EOS 行为中的作用。基于我们的 哮喘中 EOS 生物学和细胞外基质 (ECM) 的初步数据和当前理解， 目前的假设是骨膜蛋白，一种 ECM 蛋白，是由 2 型 T 辅助细胞驱动的炎症特征 细胞并在哮喘 ain/vay 中发现，是 EOS aMp2 整合素的主要粘附配体，并且 aMp2-periostin 相互作用是 EOS 功能的重要决定因素。目标 1 是定义 aMp2 的角色， 骨膜素和 TGF-P 诱导蛋白 (TGFBI)（也存在于肺中的骨膜素同源物）参与粘附、迁移、 sun/ival 以及由 IL-3、IL-5、GM-CSF 或其他激活剂激活的 EOS 的其他功能。目标 2 是 确定 aMP2 识别骨膜素的结构-功能关系，绘制 amp2 结合图 站点，并定义最小结构，当固定支持时，当可溶块时，EOS 粘附和迁移。维生素 K 依赖性 y-羧化和选择性剪接如何影响 骨膜素的生物活性也将被确定。目标 3 是了解机制并 哮喘气道中骨膜素显着增加的意义。骨膜素分泌 TGF-β或其他因子刺激的成纤维细胞和上皮细胞，及其沉积到ECM和 将分析营业额。将开发针对各种形式的骨膜素和 TGFBI 的抗体 节段性抗原激发后支气管活检中的定位。实现本提案的目标将 提供新知识并更好地理解 EOS 交易和功能以及相互作用 在 Th2 驱动的炎症中 EOS 和 ECM 之间，并将产生能够允许 这种相互作用有待研究和调节。 RELE^VANCE（参见说明）： 拟议的研究将确定结缔组织蛋白骨膜素如何强烈上调 在哮喘中受到调节，在激活时与其细胞表面受体蛋白 aMP2 整合素 (CD11b/CD18) 相互作用 EOS，支持EOS的挂载和迁移。该项目将提供新的见解 哮喘病中 EOS 的运动以及患病肺部结缔组织的生物学。