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（由申请方提供）：过敏性疾病的部分特征在于肥大细胞和嗜碱性粒细胞的活性。这些细胞结合循环IgE，随后对过敏原暴露产生反应。除了反应的IgE依赖性部分之外，细胞的表型还决定了其对细胞环境中的过敏原和其他生物分子的反应的性质。各种研究表明，嗜碱性粒细胞参与了速发型超敏反应，这是过敏性疾病的一部分。此外，在过去的3- 40年中，研究反复注意到几种嗜碱性粒细胞表型与不同的过敏性疾病状态有关。尽管嗜碱性粒细胞在速发型超敏反应中的重要性，但对各种嗜碱性粒细胞表型的基础的了解仅是粗略的。在理解这些表型方面缺乏进展的一个原因是，直到最近才充分描述了一些可能调节嗜碱性粒细胞表型的分子机制，以发展关于表型起源的假说。另一个原因是嗜碱性粒细胞很难研究，并且没有适当表征其表型的工具。该应用程序将提供一个 一套新的分析工具，以探讨嗜碱性粒细胞表型的意图，这些工具的嗜碱性粒细胞表型的问题。RNA标签是一种充分探索的表征复杂表型的方法，但由于研究这种细胞的困难，它们尚未应用于嗜碱性粒细胞表型的问题。提出了两种方法，一种是基于开发与嗜碱性粒细胞功能和表型的特定调节剂相关的定义明确的签名，第二种是基于更一般的比较，可以使用广泛的微阵列配置文件之间的自然表型。在开发出与特定嗜碱性粒细胞调节剂相关的集中特征后，该提案的第三个具体目标将检查三种充分描述的嗜碱性粒细胞表型，与奥马珠单抗治疗相关并与细胞敏感性显著增加相关的表型，与食物过敏和重度哮喘相关的自发释放表型以及与慢性特发性荨麻疹相关的抑制表型。预计对表型基础的鉴定将为驱动这些过敏性疾病的潜在生物学提供新的见解。