Galectin-3 in regulation of allergic skin inflammation

Galectin-3 调节过敏性皮肤炎症

• 批准号: 8401847
• 负责人: FU-TONG LIU
• 金额: $ 31.44万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-15 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8401847
• 关键词: Affect; Affinity; Allergic; Amino Acid Sequence; Animal Lectins; Antigens; Area; Atopic Dermatitis; Binding; Biogenesis; Biological Process; Carbohydrates; Cell Surface Proteins; Cell Surface Receptors; Cell physiology; Cell surface; Cells; Child; Chronic; Complex; Consensus; Consensus Sequence; Data; Dendritic Cells; Developed Countries; Development; Disease; Epithelial Cells; Family; Galactose Binding Lectin; Galactosides; Galectin 3; Genetically Engineered Mouse; Goals; Human; Immune response; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Interleukin-12; Lectin; Leukocytes; Mediating; Mediator of activation protein; Medical; Modeling; Molecular; Multivesicular Body; Mus; Peptide Signal Sequences; Play; Polysaccharides; Population; Prevalence; Process; Production; Proteins; Regulation; Role; Skin; Sorting - Cell Movement; T cell response; T-Cell Receptor; T-Lymphocyte; Testing; Th1 Cells; Th2 Cells; Vesicle; Work; Yeasts; allergic airway inflammation; base; carbohydrate receptor; cell type; crosslink; cytokine; extracellular; immunological synapse; in vivo; mast cell; member; mouse model; novel; novel therapeutics; protein function; public health relevance; receptor downregulation; receptor expression; response; screening; skin disorder; yeast two hybrid system

DESCRIPTION (provided by applicant): Atopic dermatitis is a common chronic inflammatory skin disease. It is a significant medical problem and as much as 15-20% of children are affected by this disease in industrialized countries. Treatment of atopic dermatitis continues to be a challenge. The current model suggests that atopic dermatitis is attributable to a Th2-mediated inflammatory response and T cells, dendritic cells, and mast cells play important roles. This proposal aims at the establishment of the role of a member of the galectin family in atopic dermatitis with the long-term goal of developing a novel therapy for treatment of this disease. Galectin-3 is a member of a family of animal lectins defined by their affinity for 2-galactosides and consensus sequences. It is expressed by a number of cell types, including epithelial cells and various leukocytes. A number of extracellular functions have been demonstrated by using exogenously added galectin-3 and these are associated with its binding to and crosslinking cell surface glycans. However, there is a great deal of evidence that endogenous galectin-3 regulates various cellular functions through intracellular actions. By studying T cells from galectin-3-deficient mice, we have demonstrated that galectin-3 is an inhibitory regulator in Th1 cells and suppresses the T cell receptor (TCR)-mediated Th1 response by promoting TCR downregulation. Galectin-3 is localized intracellularly at the immunological synapse in T cells activated by TCR engagement. We have also demonstrated that galectin-3 suppresses the production of IL-12 by dendritic cells. In addition, we have demonstrated an important role of galectin-3 in mast cells. By yeast two-hybrid screening, we found Alix as a galectin-3-binding partner, which is known to be a component of the endosomal sorting complex required for transport (ESCRT) and the multivesicular body (MVB). We also have other information suggesting that galectin-3 is associated with MVBs and exosomes. In a mouse model of atopic dermatitis, we found that galectin-3 promotes the Th2 response and suppresses the Th1 response and this is in part through the protein's function in T cells and dendritic cells. In this proposal, we plan to test the hypothesis that galectin-3 1) suppresses the TCR-mediated Th1 response by functioning at the IS; 2) is critical for the antigen-presenting function of dendritic cells by suppressing IL-12 production and functions as an exosome-associated protein; 3) promotes allergic skin inflammation through dendritic cells and mast cells (in addition to T cells).

描述（由申请人提供）：特应性皮炎是一种常见的慢性炎症性皮肤病。这是一个严重的医学问题，在工业化国家，多达15-20%的儿童受到这种疾病的影响。特应性皮炎的治疗仍然是一个挑战。目前的模型表明，特应性皮炎是由于Th 2介导的炎症反应和T细胞，树突状细胞和肥大细胞发挥重要作用。该提案旨在确定半乳糖凝集素家族成员在特应性皮炎中的作用，长期目标是开发治疗这种疾病的新疗法。半乳糖凝集素-3是动物凝集素家族的一员，由其对2-半乳糖苷和共有序列的亲和力定义。它由许多细胞类型表达，包括上皮细胞和各种白细胞。已经通过使用外源添加的半乳糖凝集素-3证明了许多细胞外功能，这些功能与其结合和交联细胞表面聚糖有关。然而，有大量证据表明内源性半乳糖凝集素-3通过细胞内作用调节各种细胞功能。通过研究来自半乳糖凝集素-3缺陷小鼠的T细胞，我们已经证明半乳糖凝集素-3是Th 1细胞中的抑制性调节剂，并且通过促进TCR下调来抑制T细胞受体（TCR）介导的Th 1应答。半乳糖凝集素-3位于细胞内由TCR接合激活的T细胞中的免疫突触处。我们还证明了半乳糖凝集素-3抑制树突状细胞产生IL-12。此外，我们已经证明了半乳糖凝集素-3在肥大细胞中的重要作用。通过酵母双杂交筛选，我们发现阿利克斯作为半乳糖凝集素-3结合伴侣，这是已知的内体分选复合物所需的运输（ESCRT）和多泡体（MVB）的组成部分。我们还有其他信息表明半乳糖凝集素-3与MVB和外来体相关。在特应性皮炎的小鼠模型中，我们发现半乳糖凝集素-3促进Th 2应答并抑制Th 1应答，这部分是通过蛋白质在T细胞和树突状细胞中的功能实现的。在该提案中，我们计划测试以下假设：半乳糖凝集素-3 1）通过在IS处起作用而抑制TCR介导的Th 1应答; 2）通过抑制IL-12产生并作为外泌体相关蛋白起作用而对树突状细胞的抗原呈递功能至关重要; 3）通过树突状细胞和肥大细胞（除了T细胞之外）促进过敏性皮肤炎症。