Placental Protein 14 as a Lectin-Like Immunomodulator

描述(由申请人提供) 这项建议侧重于胎盘蛋白14(PP14)免疫调节活性的分子和细胞机制。它建立在我们团队的一系列发现的基础上，得到了NIH R01 AI38960(于2000年竞争性更新)的支持，确立了1)PP14是少数几种直接作用于T细胞的免疫调节蛋白之一，2)它通过一种明显独特的基于T细胞激活阈值调节的免疫调节机制来实现这一点。尽管NIH R01AI38960已经资助的机制研究主要集中在PP14对TCR信号通路的影响上，而FIRCA应用的具体目的是建立在我们对PP14的S凝集素样作用模式及其对抗原提呈细胞：T细胞接触位点的影响的重要新见解的基础上。此外，这一机制下的资金将使我们能够利用以色列已有的一项新技术，以高通量分析碳水化合物结合的特异性。这两个具体目标是：1)探索PP14(通过GlycoChip TM技术)识别的精确的碳水化合物结构(S)，并结合这一分析，确定PP14‘S的碳水化合物结合谱是否与其表面碳水化合物显示不同的不同亚群和激活状态的T细胞结合相关；以及2)测试PP14通过诱导APC：T细胞接触部位形成PP14-糖蛋白晶格来发挥功能的假说，在那里它影响“免疫突触”的形成和受体聚集。FIRCA下拟议的研究重点是PP14的S新发现的凝集素样属性，应有助于新兴的蛋白质-多糖相互作用领域，并阐明这些相互作用调节免疫系统功能的方式。此外，这一研究路线可能使我们更接近PP14治疗自身免疫性疾病和移植排斥的可能治疗用途。

DESCRIPTION (provided by applicant) This proposal focuses upon the molecular and cellular mechanisms underlying the immunoregulatory activity of placental protein 14 (PP14). It builds upon a series of findings from our groups, supported by NIH R01 AI38960 (which was competitively renewed in 2000), establishing that 1) PP14 is one of only a handful of immunoregulatory proteins that act directly on T cells, and 2) it accomplishes this by an apparently unique immunoregulatory mechanism based upon T cell activation threshold modulation. Whereas the mechanistic studies already funded under NIH R01 AI38960 focus on PP14 effects on the TCR signaling pathway, the specific aims of this FIRCA application build specifically on our significant new insights into PP14's lectin-like mode of action and its impact on antigen-presenting cell (APC):T cell contact sites. Moreover, funding under this mechanism will allow us to leverage a new technology that has become available in Israel for high-throughput profiling of carbohydrate-binding specificities. The two specific aims are: 1) to explore the precise carbohydrates structure(s) recognized by PP14 (via GlycoChip TM technology), and in conjunction with this analysis, to determine whether PP14's carbohydrate-binding profile correlates with binding to T cells of different subsets and activation states that are known to differ in their surface carbohydrate displays; and 2) to test the hypothesis that PP14 functions by inducing the formation of PP14-glycoprotein lattices at APC:T cell contact sites, where it impacts the formation of "immune synapses" and receptor clustering. The proposed studies under this FIRCA, focusing on PP14's newly-discovered lectin-like property, should contribute to the emerging field of protein-glycan interactions and shed light on the way these interactions regulate the function of the immune system. Moreover, this line of investigation may bring us closer to possible therapeutic uses of PP14 for treating autoimmune disorders and transplant rejection.