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: 8254064
• 负责人: Santa Jeremy Ono
• 金额: $ 35.78万
• 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 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8254064
• 关键词: Roles; CC; chemokine; activity; mast

DESCRIPTION (provided by applicant): 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-11, 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-11-CCR1 signaling in mast cell activation in vivo; 3) to identify proteins that mediate the mast cell effects of MIP-11-IgE costimulation in vivo; and 4) to identify gene products that, when upregulated, mediate the mast cell effects of MIP-11-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-11, 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-11-CCR1 activity, specifically vimentin and PI3K3, 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-11-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. PUBLIC HEALTH RELEVANCE: Allergies are a major health problem in the United States, yet the molecular mechanisms contributing to allergic responses remain poorly defined. In this study, we will address the roles of mast cell chemokine signaling in allergic conjunctivitis. Our in vitro and in vivo techniques will clarify the roles of eotaxin-1-CCR3 signaling and MIP-11-CCR1 signaling in mast cells, and will identify relevant downstream mediators of Fc5RI- CCR1 co-activation that might serve as potential targets for novel therapies.

描述（由申请人提供）：过敏是美国的主要健康问题，降低了质量和生活，并导致了巨大的医疗保健费用。在美国，眼部过敏会影响多达五分之一的人。过敏性疾病显然需要改进和新颖的治疗方法。肥大细胞在眼部过敏中起关键作用，但是驱动肥大细胞激活的确切分子机制知之甚少。眼部超敏反应所必需的分子 - 可能是眼睛过敏治疗的合适靶标 - 包括趋化因子Eotaxin -1和MIP -11，其各自的受体CCR3和CCR1以及由这些信号调节的分子。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的作用。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剂作用； 2）探索MIP-11-CCR1信号传导在体内肥大细胞激活中的共刺激作用； 3）鉴定体内MIP-11-IgE costumulation的肥大细胞作用的蛋白质； 4）确定在上调时介导体内MIP-11-IgE共刺激的肥大细胞效应的基因产物。评估体内肥大细胞活性的收养转移模型将用作所有四个目标的组成部分。在该模型中，具有感兴趣基因型的肥大细胞被注入肥大细胞缺陷型小鼠，这些小鼠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无法恢复对眼部过敏原的早期和/或晚期反应。对于前两个目的，缺乏Eotaxin-1，MIP-11，CCR1或CCR3的肥大细胞将用于肥大细胞分化和功能的体外测定，以及体内收养转移模型。对于第三个目的，将使用体外桅杆细胞分析和体内收养转移模型评估MIP-11-CCR1活性的潜在蛋白质组学介质的作用。对于第四个目标，将使用体外桅杆细胞分析和体内产卵转移模型评估MIP-11-CCR1活性（特别是CCL7和RGS1）的转录上调介体的作用。这些研究的结果将更好地理解趋化因子信号在肥大细胞功能和眼过敏中的作用，并可以确定治疗策略的新目标。公共卫生相关性：在美国，过敏是一个主要的健康问题，但是导致过敏反应的分子机制仍然很差。在这项研究中，我们将解决肥大细胞趋化因子信号传导在过敏性结膜炎中的作用。我们的体外和体内技术将阐明Eotaxin-1-CCR3信号传导和MIP-11-CCR1信号在肥大细胞中的作用，并将确定可能作为新疗法的潜在靶标的FC5RI-CCR1共激活的相关下游介体。