Molecular profiling and immunomodulatory interventions

分子谱分析和免疫调节干预措施

基本信息

批准号：
7284805
负责人：
abraham na shaked
金额：
$ 278.02万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
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/7284805
关键词：
Abdomen Acute Address Adult Affect Age Allografting Biochemical Biological Assay Biopsy Biopsy Specimen Blood Cells Bronchoalveolar Lavage CD3 Antigens Calcineurin inhibitor Candidate Disease Gene Caring Cells Cellular Immunity Characteristics Chest Childhood Clinical Clinical Research Cohort Studies Cytokine Gene Data Databases Detection Development Diagnosis Diagnostic Disease Fibrosis Functional disorder Gene Chips Gene Expression Gene Expression Profiling Genes Goals Health Heart Hepatitis C virus Histologic Human IL2RA gene Immune Immune response Immunity Immunosuppression Incidence Individual Inflammation Inflammatory Inflammatory Response Injury Institutes Intercellular adhesion molecule 1 Interleukin-1 Interleukin-6 Intervention Invasive Investigation Ischemia Kidney Kidney Transplantation Kinetics Knowledge Laboratories Literature Liver Lung Lung Transplantation Measurement Mediating Messenger RNA Methods Modality Modeling Molecular Molecular Analysis Molecular Profiling Monitor Natural Immunity Natural regeneration Nucleic Acids Observational Study Operative Surgical Procedures Organ Organ Transplantation Outcome Pathway interactions Patients Perfusion Physiological reperfusion Polymerase Chain Reaction Population Population Study Postoperative Period Process Proteins Protocols documentation Recurrence Recurrent disease Reperfusion Therapy Research Design Research Personnel Respiratory physiology Risk Risk Factors Rodent Sampling Score Screening procedure Severities Severity of illness Site Solid Specificity Steroids Technology Testing Therapeutic immunosuppression Time Transcript Transplant Recipients Transplantation Up-Regulation Upper arm Urine Viral Load result Week Withdrawal base clinical Diagnosis clinical application cohort concept cytokine cytotoxic day delayed graft function design experience functional outcomes graft function granzyme B immune function improved kidney allograft liver allograft liver biopsy liver transplantation lung allograft mRNA Expression novel therapeutics perforin prevent response urinary

项目摘要

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）：我们提出基因表达谱，用于表征与实体器官移植相关的先天免疫和适应性免疫。我们还建议进行干预试验，以解决未满足的关键需求；临床研究以机制研究为基础。我们的建议受到我们的单中心研究和不断发展的文献的启发，即外周血细胞、泌尿细胞和支气管肺泡灌洗 (BAL) 细胞的 mRNA 分析可诊断同种异体移植物状态。我们对术中肾同种异体移植活检标本的 mRNA 图谱的鉴定可预测急性排斥反应和肾同种异体移植功能结果，这为我们的研究设计提供了信息。我们建议开展多部位肾脏特异性和多器官合作研究，以确定炎症和免疫反应是否存在共同的分子谱特征，这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。在同种异体肾移植受者中，我们将研究是否：（a）可以通过尿细胞的连续 mRNA 分析来预测急性排斥反应； (b) 基于 mRNA 谱的先发性治疗可预防急性排斥反应并保留 GFR，(c) mRNA 谱可用于指导免疫抑制管理，例如在稳定受者中停用钙调神经磷酸酶抑制剂。对不同组移植器官的研究将集中于获取前供体和移植后受者的器官特异性和非特异性损伤途径的分子分析，及其对器官功能和同种异体反应性的影响。更集中的研究将在肺和肝脏环境中进行。在肺同种异体移植中，我们将探讨：(a) 供体和受体 BAL 细胞获得的细胞 mRNA 分析是否可以预测不良后果，例如严重炎症和移植物功能受损的发展，(b) 是否遵循 BAL 细胞的持续炎症特征通过急性拒绝签名。在同种异体肝移植中，我们将探讨：(a) 促炎基因的独特 mRNA 谱所表明的早期炎症反应是否与 HCV 复发相关，以及 (b) 类固醇避免方案是否会下调表达强烈炎症特征的移植物中的 HCV 复发。这些机制测定将使用动态（实时）定量 PCR 测定进行，并在选定的情况下使用基于核酸的微阵列以及基因表达位点的免疫组织学分析，并且预计产生的数据将应用于移植人群的常规临床护理。