Human Basophil Phenotypes and Therapeutic Outcomes

人类嗜碱性粒细胞表型和治疗结果

• 批准号: 8707080
• 负责人: Donald W MacGlashan
• 金额: $ 44.47万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8707080
• 关键词: Accounting; Acute; Address; Allergens; Allergic; Allergic Disease; Allergic Reaction; Asthma; Basophils; Binding; Biological; Biology; Cells; Characteristics; Chronic; Clinical; Complex; Development; Environment; Food Hypersensitivity; General Population; Genes; Goals; Human; IgE; Immediate hypersensitivity; Interleukin-3; Lead; Link; Mediating; Messenger RNA; Molecular; Nature; Outcome; Participant; Pathogenesis; Patients; Pharmaceutical Preparations; Phenotype; Pilot Projects; Process; RNA; Reaction; Series; Therapeutic; Transcript; Urticaria; analytical tool; atopy; base; clinical phenotype; comparative; cytokine; in vivo; insight; mast cell; novel strategies; omalizumab; response; tool

DESCRIPTION (provided by applicant): Allergic diseases are characterized, in part, by the activities of mast cells and basophils. These cells bind circulating IgE and subsequently become responsive to allergen exposure. In addition to this IgE-dependent part of the reaction, the phenotype of the cell also determines the nature of its responses to both allergens and other biological molecules in the environment of the cell. A variety of studies have implicated the basophil in the immediate hypersensitivity reactions that are part of the allergic condition. In addition, studies during the last 3-4 decades have repeatedly made note of several basophil phenotypes that track with different allergic disease states. Despite the importance of the basophil in immediate hypersensitivity reactions, there have been only cursory efforts to understand the basis for the various basophil phenotypes. One reason for the lack of progress in understanding these phenotypes is that only recently are some of the molecular mechanisms that may modulate the basophil phenotype described well enough to develop hypotheses regarding the phenotypes' origins. Another reason is that the basophil is difficult to study and the tools to properly characterize its phenotype are not available. This application will provide a new set of analytical tools to explore basophil phenotypes with the intent of applying these tools to the question of basophil phenotypes. RNA signatures are a well- explored approach to characterizing complex phenotypes but they have not been applied to the question of basophil phenotypes due to the difficulties studying this cell. Two approaches are proposed, one based on developing well-defined signatures associated with specific modulators of basophil function and phenotype and the second based on the more general comparisons that can be made between natural phenotypes using a broad-based microarray profile. After developing the focused signatures that are associated with specific basophil modulators, the third specific aim of the proposal will examine three well described basophil phenotypes, the phenotype associated with omalizumab treatment and linked to marked increases in cellular sensitivity, the spontaneous release phenotype associated with food allergies and severe asthma and the suppressed phenotype associated with chronic idiopathic urticaria. It is expected that identification of the basis for the phenotypes will provide new insights into the underlying biolog that drives these allergic conditions.

描述（由申请人提供）：过敏性疾病的一部分是由肥大细胞和嗜碱性粒细胞的活性来表征的。这些细胞结合循环IgE，随后对过敏原暴露有反应。除了反应的这一IgE依赖性部分外，细胞的表型还决定了其对过敏原和细胞环境中其他生物分子的反应的性质。各种研究都暗示了嗜碱性粒细胞的直接性高敏反应，这是过敏性疾病的一部分。此外，在过去的3-4年中，研究反复记录了几种跟踪具有不同过敏性疾病状态的嗜碱性粒细胞表型。尽管嗜碱性粒细胞在直接过敏反应中的重要性，但仍有粗略的努力来理解各种嗜碱性粒细胞型的基础。理解这些表型缺乏进展的原因之一是，直到最近才是一些分子机制，这些机制可能调节嗜碱性粒细胞表型的描述足以很好地发展有关表型起源的假设。另一个原因是嗜碱性粒细胞很难研究，并且无法获得正确表征其表型的工具。该应用程序将提供 新的分析工具探索嗜碱性粒细胞表型，目的是将这些工具应用于嗜碱性粒细胞表型问题。 RNA签名是表征复杂表型的一种探索良好的方法，但由于研究该细胞的困难，它们尚未应用于嗜碱性粒细胞表型问题。提出了两种方法，一种基于与嗜碱性粒子功能和表型的特定调节剂相关的定义明确的特征，第二种基于一种基于更一般的比较，可以使用基于广泛的微阵列在自然表型之间进行比较。在开发了与特定嗜碱性粒细胞调节剂相关的聚焦特征之后，该提案的第三个特定目的将检查三种描述良好的嗜碱性粒细胞表型，与omalizumab治疗相关的表型，以及与细胞敏感性的显着增加相关的表型，与食物过敏和抑制式炎症的纯素蛋白质相关的自发释放表型相关。可以预期，表型基础的识别将为驱动这些过敏状况的基本生物学提供新的见解。