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: 6581043
• 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/6581043
• 关键词: CD antigens; Japan; T cell receptor; T lymphocyte; annexins; binding sites; biological signal transduction; carbohydrate structure; cellular immunity; clinical research; confocal scanning microscopy; cooperative study; crosslink; glycoproteins; glycosylation; human tissue; immunomodulators; immunoprecipitation; intermolecular interaction; lectin; leukocyte activation /transformation; placenta; protein binding; protein structure function

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.

描述（由申请人提供） 该建议侧重于胎盘蛋白14（PP14）免疫调节活性的基础的分子和细胞机制。它基于我们小组的一系列发现，由NIH R01 AI38960（在2000年进行了竞争性更新）的支持，确定1）PP14是直接在T细胞上作用于T细胞的少数免疫调节蛋白之一，并且2）基于这一明显的唯一的免疫机制，以此来实现这一目标。尽管已经在NIH R01 AI38960下资助的机械研究侧重于PP14对TCR信号通路的影响，但该FIRCA应用程序的特定目的是我们针对我们对PP14的凝集素样作用方式的重要新见解及其对抗原抗原呈现方式的影响及其对抗原抗原呈递细胞（APC）的影响。此外，这种机制下的资金将使我们能够利用一项新技术，该技术已在以色列提供，用于碳水化合物结合特异性的高通量分析。这两个具体目的是：1）探索PP14认可的精确碳水化合物结构（通过Glycochip TM技术），并结合此分析，以确定PP14的碳水化合物结合曲线与与不同子集和激活状态的结合在其表面含量差异的情况下与与T细胞的结合是否相关，以表面含量与其表面含量不同。 2）为了测试PP14通过在APC：T细胞接触位点诱导PP14-糖蛋白晶格的形成来实现的假设，在此影响它影响“免疫突触”和受体聚类的形成。该FIRCA下的拟议研究重点介绍了PP14新发现的类似凝集素样性质，应有助于蛋白质 - 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，这种调查可能会使我们更接近PP14在治疗自身免疫性疾病和移植抑制的可能治疗用途。