PLACENTAL PROTEIN 14 AS A UNIQUE IMMUNOREGULATOR

描述：(改编自调查人员的摘要)这项工作的目标 格兰特在下一个资助期将分析免疫调节 胎盘蛋白14(PP14)的更深层次的性质以及设计和 评价具有免疫治疗潜力的PP14衍生物。这是竞争激烈的 续签申请建立在我们实验室在 之前的资助期，首次显示出PP14直接抑制 T细胞，建立了PP14‘S独特的“抗流变”作用机制 提高T细胞受体激活阈值，开发出第一个 PP14的重组衍生物，定义了PP14‘S分子结合势， 并克隆和鉴定了动物PP14同源物。根据我们的小说改编 对PP14的S函数性质的洞察，我们现在假设PP14可能 解释怀孕的一些免疫现象，如向 妊娠妇女Th2细胞因子的分泌和临床改善 患有某些自身免疫性疾病。考虑到这一点，我们打算 转向以PP14为基础的免疫疗法，以抑制致病T细胞。 具体目标是：1)确定淋巴细胞的表型和命运 被PP14抑制；2)阐明PP14介导的T细胞的分子机制 细胞抑制，目的是识别关键的膜受体(S)和 PP14对细胞内信号通路(S)的影响；3)设计 具有增强功能的PP14的重组衍生物，并探索其 自身免疫和同种异体免疫动物疾病模型的治疗应用。这个 建议的研究结合了基本特征和应用特征。

DESCRIPTION: (Adapted from the investigator's abstract) The objectives of this grant in the next funding period will be to analyze the immunoregulatory properties of placental protein 14 (PP14) in greater depth and to design and evaluate PP14 derivatives with immunotherapeutic potential. This competitive renewal application builds upon a body of work from our laboratory during the prior funding period that first demonstrated a direct PP14 inhibitory effect on T cells, established PP14's unique "rheostatic" mechanism of action in elevating T cell receptor activation thresholds, developed the first recombinant derivatives of PP14, defined PP14's molecular binding potentials, and cloned and characterized animal PP14 homologues. Based upon our novel insights into PP14's functional properties, we now hypothesize that PP14 may explain some immunological phenomoena of pregnancy, such as the shift towards Th2 cytokine output and the clinical improvement documented in pregnant women suffering from certain autoimmune diseases. With this in mind, we intend to move towards PP14-based immunotherapeutics for inhibiting pathogenic T cells. The specific aims are: 1) to define the phenotype and fate of lymphocytes inhibited by PP14; 2) to elucidate the molecular mechanisms of PP14-mediated T cell inhibition, with the goal of identifying critical membrane receptor(s) and intracellular cell signaling pathway(s) influenced by PP14; and 3) to design recombinant derivatives of PP14 with enhanced functions, and to explore their therapeutic use in autoimmune and alloimmune animal disease models. The proposed studies combine basic and applied features.