Galectin-3 in regulation of allergic skin inflammation

Galectin-3 调节过敏性皮肤炎症

• 批准号: 8206814
• 负责人: FU-TONG LIU
• 金额: $ 33.09万
• 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/8206814
• 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; Screening procedure; 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; 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). PUBLIC HEALTH RELEVANCE: Atopic dermatitis is a common chronic inflammatory skin disease. The prevalence of this disease has increased by two- to three-fold during the past three decades in industrialized countries, where the current prevalence in children is estimated to be 15-20%. The treatment of this disease continues to be a challenge. Elucidation of the cellular and molecular bases of this disease is important for development of novel therapeutic strategies. Galectin-3 is a member of a family of proteins that bind carbohydrates, called lectins. The galectin family defined by their binding of 2-galactosides and sharing of similar amino acid sequences. When galectin-3 is added to various cells, it can bind to cell surface proteins that have attached carbohydrates recognizable by the lectin. However, there is a great deal of evidence that galectin-3 that is present inside the cells regulates various cellular functions through intracellular actions (without the protein being secreted). We have obtained important information on the functions of galectin-3 by studying genetically engineered mice we generated that lack galectin-3. Most recently, we found that galectin-3 plays an important function in the response of T cells. We found that galectin-3 is clustered inside the cells in the area that is important for the T cell response called the immunological synapse. We also found that galectin-3 has an important function in another cell type called dendritic cells. We have previously demonstrated that galectin-3 promotes allergic airway inflammation. We now have a significant amount of data supporting the role of this protein in a mouse model of atopic dermatitis. Additional work is required for understanding how galectin-3 regulates these inflammatory processes and for advancing strategies for developing galectin-3-targeting therapies. In this proposal, we plan to establish the mechanism by which galectin-3 regulates the responses of T cell and dendritic cell, which are both key cell types in the development of allergic skin inflammation associated with atopic dermatitis. We also plan to elucidate the cellular basis for galectin-3's regulatory role in a mouse model of atopic dermatitis.

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。这是一个重大的医疗问题，在工业化国家中，多达15-20％的儿童受这种疾病的影响。特应性皮炎的治疗仍然是一个挑战。当前的模型表明，特应性皮炎归因于Th2介导的炎症反应，T细胞，树突状细胞和肥大细胞起着重要作用。该提案旨在建立甲状腺素家族成员在特应性皮炎中的作用，其长期目标是开发一种新型治疗这种疾病的疗法。 Galectin-3是动物凝集素家族的成员，其对2-半乳糖苷和共识序列的亲和力定义。它由许多细胞类型表达，包括上皮细胞和各种白细胞。通过使用外源添加的lectectin-3，已经证明了许多细胞外功能，并且与其与和交联细胞表面聚糖的结合有关。但是，有很多证据表明内源性乳糖素3通过细胞内作用调节各种细胞功能。通过研究lectectin-3缺陷型小鼠的T细胞，我们证明了Galectin-3是TH1细胞中的抑制性调节剂，并通过促进TCR下调抑制TCR受体（TCR）介导的Th1反应。 GALECTIN-3在TCR参与激活的T细胞中的免疫突触上细胞内局部局部局部。我们还证明了lectectin-3抑制树突状细胞的IL-12产生。此外，我们已经证明了乳糖素3在肥大细胞中的重要作用。通过酵母的两杂化筛选，我们发现ALIX是甲状腺素3结合伴侣，该伴侣已知是运输（ESCRT）和多囊体（MVB）所需的内体分类复合物的组成部分。我们还有其他信息，表明Galectin-3与MVB和外泌体相关。在小鼠特应性皮炎的小鼠模型中，我们发现半乳糖素-3促进了Th2反应并抑制Th1反应，这部分通过T细胞和树突状细胞中的蛋白质功能。在该提案中，我们计划检验lectectin-3 1）通过在IS上运作来抑制TCR介导的TH1响应的假设； 2）对于树突状细胞的抗原呈递功能至关重要，通过抑制IL-12的产生和作为外泌体相关蛋白的功能； 3）通过树突状细胞和肥大细胞（除T细胞）促进过敏性皮肤炎症。 公共卫生相关性：特应性皮炎是一种常见的慢性炎症性皮肤病。在过去的三十年中，在工业化国家中，这种疾病的患病率增加了两到三倍，在工业化国家中，目前儿童的患病率估计为15-20％。这种疾病的治疗仍然是一个挑战。阐明该疾病的细胞和分子碱基对新的治疗策略的发展很重要。 Galectin-3是结合碳水化合物的蛋白质家族的成员，称为凝集素。半乳糖苷的结合和相似的氨基酸序列的共享来定义的半乳糖素家族。当将乳糖素-3添加到各种细胞中时，它可以与凝集素识别的碳水化合物结合的细胞表面蛋白结合。但是，有大量证据表明，细胞内存在的Galectin-3通过细胞内作用调节各种细胞功能（没有分泌蛋白质）。 我们通过研究基因工程的小鼠而产生的缺乏lectectin-3的基因工程小鼠获得了有关Galectin-3功能的重要信息。最近，我们发现Galectin-3在T细胞的反应中起重要功能。我们发现，半乳糖素3聚集在该区域的细胞内，这对于称为免疫突触的T细胞反应很重要。我们还发现Galectin-3在另一种称为树突状细胞的细胞类型中具有重要功能。 我们以前已经证明Galectin-3促进过敏性气道炎症。现在，我们有大量数据支持该蛋白在特应性皮炎的小鼠模型中的作用。需要进行其他工作来了解Galectin-3如何调节这些炎症过程，并为开发Galectin-3靶向疗法的策略而进行推进。 在此提案中，我们计划建立乳肠蛋白3调节T细胞和树突状细胞反应的机制，它们都是与特应性皮炎相关的过敏性皮肤炎症的发展中的关键细胞类型。我们还计划在小鼠特应性皮炎的小鼠模型中阐明Galectin-3调节作用的细胞基础。