Placental Protein 14 as a Lectin-Like Immunomodulator

描述（由申请人提供） 该建议的重点是胎盘蛋白14（PP 14）的免疫调节活性的分子和细胞机制。它建立在我们小组的一系列发现基础上，得到NIH R01 AI38960（2000年竞争性更新）的支持，确定1）PP14是直接作用于T细胞的少数免疫调节蛋白之一，2）它通过基于T细胞活化阈值调节的明显独特的免疫调节机制来实现这一点。尽管已经在NIH R01 AI38960下资助的机制研究集中在PP14对TCR信号通路的影响上，但该FIRCA申请的具体目标特别建立在我们对PP14的凝集素样作用模式及其对抗原呈递细胞（APC）的影响的重要新见解上：T细胞接触位点。此外，在这一机制下的资金将使我们能够利用一种新技术，该技术已在以色列用于碳水化合物结合特异性的高通量分析。这两个具体目标是：1）探索PP14识别的精确碳水化合物结构（通过GlycoChip TM技术），并结合该分析，以确定PP14的碳水化合物结合谱是否与结合不同亚群的T细胞和已知其表面碳水化合物展示不同的活化状态相关;和2）检验PP14通过在APC：T细胞接触位点诱导PP14-糖蛋白晶格的形成而起作用的假设，在APC：T细胞接触位点，PP14影响"免疫突触"和受体聚集的形成。FIRCA下的拟议研究，重点是PP14新发现的凝集素样特性，应该有助于蛋白质-聚糖相互作用的新兴领域，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.