Signaling and Cell Biology of TIM-1

描述(申请人提供)：跨膜免疫球蛋白和粘蛋白(TIM)家族的蛋白质在小鼠和人类中与多种功能有关。该家族的创始成员Tim-1最初被描述为甲型肝炎病毒(HAVcr-1)的受体。最初对TIM-1在免疫中的可能作用的兴趣集中在T细胞上，这是由于 TIM-1基因多态与辅助性T细胞对Th1或Th2细胞的承诺之间的关系。最近的研究极大地拓宽了Tim-1在免疫系统中的可能作用，包括涉及该蛋白对肥大细胞的调节，肥大细胞也与特应性疾病密切相关。我们理解Tim-1功能的方法主要集中在该蛋白下游的信号通路以及它的细胞生物学上。我们认为，这种方法是对其他体内研究的重要补充，这些研究尚未产生关于TIM-1在特应性疾病小鼠模型中的功能的一致故事。我们最近的研究已经开始揭示与T细胞中TIM-1的功能相关的有趣的生物学。在这一新的应用中，我们将继续努力确定TIM-1在T细胞上的功能，但也将扩大我们的研究范围，包括该蛋白在肥大细胞中的作用，无论是在体外还是在体内。我们认为，这份报告中概述的研究 建议有很大的潜力帮助理解体内调节TIM-1的效果，这已在哮喘的临床前模型中显示出潜力。

DESCRIPTION (provided by applicant): Proteins of the transmembrane immunoglobulin and mucin (TIM) family have been linked to a wide variety of functions in mice and humans. The founding member of the family, TIM-1, was first described as a receptor for the hepatitis A virus (HAVcr-1). Initial interest in the possible role of TIM-1 in immunity focused on T cells, due to an association between TIM-1 polymorphisms and commitment of helper T cells to either the Th1 or Th2 lineage. More recent studies have greatly broadened the possible role of TIM-1 in the immune system, including implicating this protein in the regulation of mast cells, which are also intimately involved in atopic disease. Our approach to understanding the function of TIM-1 has been to focus mainly on the signaling pathways downstream of this protein, as well as its cell biology. We believe that this approach is an important complement to the in vivo studies of others, which have yet to yield a consistent story regarding TIM-1 function in mouse models of atopic disease. Our recent studies have begun to reveal interesting biology associated with the function of TIM-1 in T cells. In this renewal application, we will continue our efforts to define te function of TIM-1 on T cells, but also broaden our studies to include investigation of the role of this protein in mast cells, both in vitro and in vivo. We believe that the studies outlined in this proposal have great potential to aid in the understanding of the effects of in vivo modulation of TIM-1, which has shown potential in pre-clinical models of asthma.