Placental Protein 14 as a Lectin-Like Immunomodulator

胎盘蛋白 14 作为凝集素样免疫调节剂

• 批准号: 6826845
• 负责人: Mark L Tykocinski
• 金额: $ 4.03万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-12-15 至 2005-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6826845
• 关键词: Placental; Protein; 14; Lectin; Like

EXCEED THE SPACE PROVIDED. 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. PERFORMANCE SITE ========================================Section End===========================================

超出所提供的空间。该提案重点关注胎盘蛋白 14 (PP14) 免疫调节活性的分子和细胞机制。它建立在我们小组的一系列发现之上，并得到 NIH R01 AI38960（于 2000 年竞争更新）的支持，确定 1) PP14 是少数直接作用于 T 细胞的免疫调节蛋白之一，2) 它通过基于 T 细胞激活阈值调节的明显独特的免疫调节机制来实现这一点。虽然 NIH R01 AI38960 资助的机制研究重点关注 PP14 对 TCR 信号通路的影响，但该 FIRCA 申请的具体目标专门建立在我们对 PP14 的凝集素样作用模式及其对抗原呈递细胞的影响的重要新见解之上。 (APC)：T 细胞接触位点。此外，该机制下的资金将使我们能够利用以色列已可用的新技术对碳水化合物结合特异性进行高通量分析。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，确定 PP14 的碳水化合物结合谱是否与不同 T 细胞的结合相关。已知其表面碳水化合物显示不同的子集和激活状态； 2) 检验以下假设：PP14 通过诱导 APC:T 细胞接触位点处 PP14-糖蛋白晶格的形成来发挥作用，从而影响“免疫突触”的形成和受体聚集。 FIRCA 下拟议的研究重点关注 PP14 新发现的凝集素样特性，应有助于蛋白质-聚糖相互作用的新兴领域，并揭示这些相互作用调节免疫系统功能的方式。此外，这一研究方向可能使我们更接近 PP14 治疗自身免疫性疾病和移植排斥的可能治疗用途。表演网站==========================================部分结束====== =======================================