Eosinophil Recruitment and Activation in Solid Tumors

实体瘤中嗜酸性粒细胞的募集和激活

• 批准号: 7006104
• 负责人: JAMES Joseph LEE
• 金额: $ 30.28万
• 依托单位: MAYO CLINIC ARIZONA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-10 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7006104
• 关键词: allergens; breast neoplasms; disease /disorder model; disease /disorder onset; eosinophil; gene expression; genetically modified animals; immunomodulators; laboratory mouse; lung disorder; metastasis; neoplasm /cancer blood supply; polymerase chain reaction

DESCRIPTION (provided by applicant): The infiltration and accumulation of eosinophils in solid tumors has been recognized as a correlative clinical feature of several tumor types, including colon, pancreatic, and breast cancers. This eosinophil recruitment also occurs in many mouse models of tumorigenesis. Despite the abundance of clinical studies and the availability of mouse models, eosinophil effector functions in general are poorly understood and, indeed, questions remain as to the role(s), if any, of these leukocytes. Studies of tumor associated eosinophils in the mouse have remained equivocal, in part, due to the lack of specific reagents and models with which to define unequivocally mechanisms of effector function. The goal of this proposal is to bridge this gap by exploiting our extensive experience examining eosinophil activities using allergen provocation models of lung disease. For example, we have created several specific antibodies that allow unambiguous detection of infiltrating eosinophils and the release of granule proteins (i.e., activation leading to degranulation). In addition, we have developed several knockout mice deficient of the predominant granule proteins that will permit assessments of degranulation. We have also developed a novel line of transgenic mice congenitally devoid of eosinophils. The ablation of eosinophils in these transgenic animals was accomplished through the expression of a suicide gene (i.e., Diphtheria Toxin A) exclusively in eosinophil-lineage cells and provides a unique opportunity to define eosinophil responses to tumors. This proposal utilizes these novel models and reagents to test the hypothesis that eosinophils modulate tumor onset/growth. Our objectives will be achieved by completing the following Specific Aims: (1) To define the kinetics of eosinophil recruitment to solid tumors as well as the extent of eosinophil activation/degranulation within tumors to which they have been attracted; (2) To determine the extent to which eosinophil-associated host responses modulate mammary gland tumor onset, growth kinetics, or rate of metastasis; (3) To determine whether eosinophil degranulation (i.e., the release of toxic cationic secondary granule proteins) has direct effects on mammary gland tumors.

描述（由申请人提供）：嗜酸性粒细胞在实体瘤中的浸润和积累已被认为是几种肿瘤类型的相关临床特征，包括结肠，胰腺和乳腺癌。这种嗜酸性粒细胞募集也发生在许多肿瘤发生的小鼠模型中。尽管大量临床研究和小鼠模型的可用性，但嗜酸性粒细胞效应子的功能一般都了解很少，实际上，关于这些白细胞的作用（如果有的话）仍然存在问题。小鼠中肿瘤相关的嗜酸性粒细胞的研究部分仍然是模棱两可的，部分原因是缺乏特定的试剂和模型来定义效应子功能的明确机制。该提案的目的是通过利用肺部疾病过敏原模型来利用我们丰富的研究嗜酸性粒细胞活动的丰富经验来弥合这一差距。例如，我们创建了几种特定的抗体，可以明确检测浸润性嗜酸性粒细胞和颗粒蛋白的释放（即激活导致脱粒化）。此外，我们开发了几只缺乏主要颗粒蛋白的敲除小鼠，这些小鼠将允许评估脱粒。我们还开发了一条新型的转基因小鼠，原始没有嗜酸性小鼠。通过表达自杀基因（即，白喉毒素A）在嗜酸性粒细胞中的细胞中的表达来实现这些转基因动物中嗜酸性粒细胞的消融，并提供了定义嗜酸性粒细胞粒细胞反应的独特机会。该建议利用这些新型模型和试剂来检验嗜酸性粒细胞调节肿瘤发作/生长的假设。我们的目标将通过完成以下特定目的来实现：（1）定义嗜酸性粒细胞募集的动力学对实体瘤的动力学以及吸引吸引的肿瘤中嗜酸性粒细胞激活/脱粒的程度； （2）确定嗜酸性粒细胞相关的宿主反应在多大程度上调节乳腺肿瘤的发作，生长动力学或转移速率； （3）确定嗜酸性粒细胞脱粒（即，有毒阳离子二次颗粒蛋白的释放）是否对乳腺肿瘤有直接影响。