Roles of CC chemokine activity in mast cell responses and ocular allergy

CC趋化因子活性在肥大细胞反应和眼部过敏中的作用

• 批准号: 8318773
• 负责人: Santa Jeremy Ono
• 金额: $ 37.3万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8318773
• 关键词: Address; Adoptive Transfer; Affect; Allergens; Allergic Conjunctivitis; Allergic Disease; Automobile Driving; Binding; Biological Assay; CC chemokine receptor 3; CCL7 gene; CCR1 gene; Cell Differentiation process; Cell physiology; Cells; Chemotaxis; Defect; Eotaxin; Gene Chips; Gene Expression Profile; Gene Targeting; Genes; Genotype; Goals; Health; Health Care Costs; Hypersensitivity; IgE; In Vitro; Macrophage Inflammatory Protein-1; Mediating; Mediator of activation protein; Modeling; Molecular; Mus; Pathogenesis; Phase; Play; Population; Production; Proteins; Proteomics; Quality of life; RGS1 gene; Reaction; Role; Signal Transduction; Stimulus; Surface; Symptoms; Techniques; Testing; United States; Vimentin; allergic response; beta-Chemokines; chemokine; crosslink; cytokine; improved; in vitro Assay; in vivo; interest; mast cell; new therapeutic target; novel; reconstitution; response

Allergies are a major health problem in the United States, reducing quality and life and resulting in significant health care costs. Ocular allergies affect as many as one in five people in the United States. Improved and novel treatments are clearly needed for allergic diseases. Mast cells play a critical role in ocular allergy, but the exact molecular mechanisms driving mast cell activation are poorly understood. Molecules that are necessary for ocular hypersensitivity reactions - and that might be suitable targets for treatments of ocular allergy - include the chemokines eotaxin-1 and MIP-1¿, their respective receptors CCR3 and CCR1, and molecules regulated by these signals. The goal of the study outlined below is to better define the roles of these molecules in ocular allergy. The study contains the following specific aims: 1) to examine the mast cell-priming role of eotaxin-1-CCR3 activity in a murine model of allergic conjunctivitis; 2) to explore the costimulatory role of MIP-1¿-CCR1 signaling in mast cell activation in vivo; 3) to identify proteins that mediate the mast cell effects of MIP-1¿-IgE costimulation in vivo; and 4) to identify gene products that, when upregulated, mediate the mast cell effects of MIP-1¿-IgE costimulation in vivo. The adoptive transfer model for assessing in vivo mast cell activity will be used as a component of all four aims. In this model, mast cells with a genotype of interest are injected into mast cell-deficient mice, which have a defective ocular allergy response. Reconstituted mast cell populations lacking critical genes will fail to restore early-phase and/or late-phase responses to ocular allergens. For the first two aims, mast cells deficient for eotaxin-1, MIP-1¿, CCR1 or CCR3 will be used for in vitro assays of mast cell differentiation and function, and for the in vivo adoptive transfer model. For the third aim, the roles of potential proteomic mediators of MIP-1¿-CCR1 activity, specifically vimentin and PI3K¿, will be assessed using the in vitro mast cell assays and in vivo adoptive transfer model. For the fourth aim, the roles of transcriptionally upregulated mediators of MIP-1¿-CCR1 activity, specifically CCL7 and RGS1, will be assessed using the in vitro mast cell assays and in vivo adoptive transfer model. The results of these studies will provide a better understanding of the roles of chemokine signaling in mast cell function and ocular allergy, and may identify novel targets for therapeutic strategies.

过敏是美国的一个主要健康问题，降低了质量和生活， 医疗保健费用。在美国， 美国的对于过敏性疾病，显然需要改进的和新的治疗。桅杆 肥大细胞在眼部变态反应中起着关键作用，但驱动肥大细胞的确切分子机制 激活机制知之甚少。眼超敏反应所必需的分子 可能是治疗眼过敏的合适靶点的反应包括 趋化因子eotaxin-1和MIP-1，它们各自的受体CCR 3和CCR 1，以及分子 受这些信号的影响。下文概述的研究目标是更好地界定 这些分子在眼部过敏中的作用。本研究的具体目的如下：（1）研究 嗜酸性粒细胞趋化因子-1-CCR 3活性在变应性结膜炎小鼠模型中的肥大细胞启动作用; 2)探讨MIP-1 <$-CCR 1信号通路在肥大细胞活化中的共刺激作用; 鉴定体内介导MIP-1-IgE共刺激的肥大细胞效应的蛋白质;以及4） 鉴定当上调时介导MIP-1 <$-IgE的肥大细胞效应的基因产物 体内共刺激。用于评估体内肥大细胞活性的过继转移模型将是 作为四个目标的一部分。在该模型中，将具有感兴趣基因型的肥大细胞 注射到肥大细胞缺陷小鼠中，其具有缺陷的眼部过敏反应。 缺乏关键基因的重构肥大细胞群将不能恢复早期和/或晚期肥大细胞。 对眼部过敏原的晚期反应。对于前两个目标，缺乏肥大细胞， eotaxin-1、MIP-1、CCR 1或CCR 3将用于肥大细胞分化的体外测定， 功能，并用于体内过继转移模型。对于第三个目标，潜在的角色 将评估MIP-1 <$-CCR 1活性的蛋白质组学介质，特别是波形蛋白和PI 3 K <$ 使用体外肥大细胞测定和体内过继转移模型。第四个目标， MIP-1 <$-CCR 1活性的转录上调介质，特别是CCL 7和 将使用体外肥大细胞试验和体内过继转移模型评估RGS 1。 这些研究的结果将有助于更好地理解趋化因子的作用 肥大细胞功能和眼过敏的信号传导，并可能确定新的治疗目标， 战略布局