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.

在美国，过敏是一个主要的健康问题，降低了质量和生活，并产生 在巨大的医疗保健费用中。眼部过敏会影响多达五分之一的人 美国。过敏性疾病显然需要改进和新颖的治疗方法。桅杆 细胞在眼过敏中起关键作用，但是确切的分子机制驱动肥大细胞 激活知之甚少。眼部超敏反应所必需的分子 反应 - 这可能是眼睛过敏治疗的合适靶标 - 包括 趋化因子Eotaxin-1和MIP-1，其相对受体CCR3和CCR1以及分子 由这些信号调节。下面概述的研究的目的是更好地定义 这些分子在眼过敏中。该研究包含以下特定目的：1）检查 eotaxin-1-CCR3活性在过敏性结膜炎模型中的肥大细胞蛋白酶作用； 2）探索MIP -1？-CCR1信号在体内肥大细胞激活中的共刺激作用； 3） 鉴定介导体内MIP -1- costumulation的肥大细胞作用的蛋白质；和4） 确定更新后介导MIP -1— IGE的肥大细胞效应的基因产品 体内共刺激。用于评估体内肥大细胞活性的自适应转移模型将是 用作所有四个目标的组成部分。在此模型中，具有感兴趣基因型的肥大细胞是 注射成肥大细胞缺陷小鼠，它们的眼部过敏反应有缺陷。 缺乏关键基因的重构肥大细胞群将无法恢复早期和/或 对眼过敏原的晚期反应。对于前两个目的，肥大细胞不足 Eotaxin-1，MIP-1？，CCR1或CCR3将用于肥大细胞分化和 功能，以及体内自适应转移模型。为了第三个目标，潜力的作用 将评估MIP -1。的蛋白质组学介体，特别是波形蛋白和PI3K？ 使用体外肥大细胞分析和体内自适应转移模型。对于第四个目标 MIP -1。ccr1活动的转录更新介质的角色，特别是CCL7和 RGS1将使用体外肥大细胞测定和体内自适应转移模型进行评估。 这些研究的结果将更好地了解趋化因子的作用 肥大细胞功能和眼过敏中的信号传导，可以识别治疗的新靶 策略。