Molecular profiling and immunomodulatory interventions

分子谱分析和免疫调节干预措施

• 批准号: 6875931
• 负责人: abraham na shaked
• 金额: $ 230.53万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-15 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6875931
• 关键词: biomarker; calcineurin; clinical research; cooperative study; disease /disorder prevention /control; disease /disorder proneness /risk; enzyme inhibitors; gene expression; gene expression profiling; hepatitis C; homologous transplantation; human subject; immune response; immunocytochemistry; immunogenetics; immunomodulators; immunopharmacology; immunosuppression; immunotherapy; inflammation; longitudinal human study; messenger RNA; microarray technology; patient oriented research; transplant rejection; transplantation; transplantation immunology

DESCRIPTION (provided by applicant): We propose gene expression profiling for the characterization of innate immunity and adaptive immunity pertinent to solid organ transplantation. We also propose interventional trials that will address critical unmet needs; the clinical studies are underpinned by mechanistic studies. Our proposals were stimulated by our single center studies and evolving literature that mRNA profiling of peripheral blood cells, urinary cells, and bronchoalveolar lavage (BAL) cells are diagnostic of allograft status. Our identification of mRNA profiles of intraoperative renal allograft biopsy specimens that predict acute rejection and renal allograft functional outcome has informed our research design. We propose cooperative multi-site kidney-specific and multi-organ studies to determine whether there is common molecular profile characteristic of inflammatory and immune responses, and which can provide a better method to monitor function and apply interventional modalities aimed at improving graft outcome. In renal allograft recipients, we will investigate whether: (a) acute rejection can be predicted by sequential mRNA profiling of urinary cells; (b) preemptive treatment, based on mRNA profiles, prevents acute rejection and preserves GFR, and (c) mRNA profiles can be used to guide immunosuppression management, such as the withdrawal of calcineurin inhibitors in stable recipients. Studies in diverse groups of transplanted organs will center on the molecular profiling of organ specific and nonspecific injury pathways in the donor prior to procurement and in the recipient immediately after transplantation, and their impact on organ function and alloreactivity. More focused studies will be done in the lung and the liver setting. In lung allografts, we will explore: (a) whether mRNA profiling of cells obtained by donor and recipient BAL cells predict adverse outcomes such as intense inflammation and development of impaired graft function, (b) whether a persistent inflammatory signature of BAL cells is followed by an acute rejection signature. In liver allografts, we will explore: (a) whether an early inflammatory response indicated by a unique mRNA profile of proinflammatory genes is correlated with HCV recurrence, and (b) whether a steroid-avoidance protocol downregulates HCV recurrence in grafts expressing intense inflammatory signature. These mechanistic assays will be carried out with the use of kinetic (real) time quantitative PCR assay, and in select instances with the use of nucleic-acid based microarrays, as well as immunohistologic analysis of the site of gene expression, and are expected to yield data that will be applied in routine clinical care of the transplanted population.

描述（由申请人提供）：我们提出了基因表达分析，以表征与固体器官移植有关的先天免疫和适应性免疫。我们还提出了将解决关键未满足需求的介入试验；临床研究以机械研究为基础。我们的提案是通过单一中心研究和不断发展的文献刺激的，即外周血细胞，尿细胞和支气管肺泡灌洗（BAL）细胞的mRNA分析是同种异体移植状态的诊断。我们对预测急性排斥反应和肾脏同种异体功能结果的术中同种异体移植活检标本的mRNA谱的鉴定为我们的研究设计提供了信息。我们提出合作的多站点肾脏特异性和多器官研究，以确定炎症和免疫反应的共同分子谱特征，并且可以提供更好的方法来监测功能并应用旨在改善移植结果的介入方式。 在同种异体移植受体中，我们将研究是否可以通过尿细胞的顺序mRNA分析来预测急性排斥； （b）基于mRNA概况的先发治疗可防止急性排斥并保留GFR，并且（c）mRNA谱可用于指导免疫抑制管理，例如在稳定受体中撤回钙调神经素抑制剂。 在各种移植器官中进行的研究将集中在供体之前的器官特异性和非特异性损伤途径的分子分析上，并在移植后立即在接受者和受体中，以及它们对器官功能和异种反应性的影响。将在肺部和肝脏环境中进行更多重点的研究。在肺同种异体移植物中，我们将探索：（a）供体和受体BAL细胞获得的细胞的mRNA分析是否能够预测不良结果，例如强烈的炎症和受损的移植功能的发展，（b）BAL细胞的持续性炎症性信号是否在BAL细胞中得到急性抑制标志。 在同种异体移植物中，我们将探索：（a）促炎基因的独特mRNA特征表明的早期炎症反应是否与HCV复发相关，以及（b）（b）类固醇避免的方案是否下调了表达强烈炎症症状的移植物中的HCV再生。 这些机械测定法将使用动力学（真）定量PCR测定法进行，并在使用基于核酸的微阵列以及对基因表达部位的免疫组织学分析的选择中进行，并有望在接受移植群体的常规临床护理中产生数据。