Human Basophil Phenotypes and Therapeutic Outcomes

描述（由申请人提供）：过敏性疾病的部分特征是肥大细胞和嗜碱性细胞的活动。这些细胞结合循环IgE，随后对过敏原暴露产生反应。除了这种依赖于ige的反应部分，细胞的表型也决定了其对细胞环境中过敏原和其他生物分子的反应性质。各种各样的研究表明，嗜碱性粒细胞参与了过敏条件下的直接超敏反应。此外，过去3-4年的研究已经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即时超敏反应中很重要，但对于了解各种嗜碱性粒细胞表型的基础，人们只做了粗略的努力。在理解这些表型方面缺乏进展的一个原因是，直到最近才有一些可能调节嗜碱性粒细胞表型的分子机制被描述得足够好，足以形成关于表型起源的假设。另一个原因是嗜碱性粒细胞难以研究，并且没有适当表征其表型的工具。这个应用程序将提供一个

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.