Human Basophil Phenotypes and Therapeutic Outcomes

描述(申请人提供)：过敏性疾病的特征部分是肥大细胞和嗜碱性粒细胞的活动。这些细胞结合循环中的IgE，随后对过敏原暴露产生反应。除了这个依赖于IgE的反应部分，细胞的表型还决定了它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，嗜碱性细胞参与了作为过敏条件一部分的即刻超敏反应。此外，在过去3-40年的研究中，反复注意到几种碱性粒细胞表型跟踪不同的过敏性疾病状态。尽管嗜碱性粒细胞在即刻超敏反应中很重要，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，一些可能调节嗜碱性粒细胞表型的分子机制才被描述得足够好，足以形成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，也没有合适的工具来表征它的表型。此应用程序将提供一个 探索嗜碱粒细胞表型的一套新的分析工具，目的是将这些工具应用于嗜碱粒细胞表型的问题。RNA签名是一种很好地描述复杂表型的方法，但由于研究嗜碱性细胞的困难，它们还没有被应用到嗜碱性粒细胞表型的问题上。提出了两种方法，一种基于开发与碱性粒细胞功能和表型的特定调节器相关的明确定义的特征，第二种基于使用广泛的微阵列配置文件可以在自然表型之间进行更一般的比较。在开发出与特定的嗜碱性粒细胞调节剂相关的聚焦信号后，该提案的第三个具体目标将检查三种描述良好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，与食物过敏和严重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。预计表型基础的鉴定将为驱动这些过敏性疾病的潜在Biolog提供新的见解。

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.