Differential Gene Expression

差异基因表达

• 批准号: 7280807
• 负责人: Daniel R. Salomon
• 金额: $ 46.84万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7280807
• 关键词: artificial immunosuppression; biopsy; biotechnology; cooperative study; functional /structural genomics; gene expression; human subject; kidney disorder; kidney transplantation; longitudinal human study; lymphocyte; microarray technology; patient oriented research; phenotype; postoperative complications; proteomics; transplant rejection; transplantation immunology

Despite recent reductions in the incidence of acute rejection, chronic allograft nephropathy and immunosuppressive drug side effects are still major causes of graft loss and patient morbidity. In this context, it is essential to advance our understanding of the immune response and the responses of the transplanted organ to both immune and non-immune injury mechanisms. Analysis of gene expression is one means to identify molecular pathways involved in transplantation biology. The objective of Project 1 is to use high-density microarray technology to measure differential gene expression in kidney biopsies and peripheral blood of patients with well-defined phenotypes: acute rejection, chronic allograft nephropathy and patients biopsied by protocol at 12 to 24 months with well-functioning kidney transplants. Our preliminary data based on studies of almost 100 subjects demonstrates characteristic gene expression profiles in biopsies and peripheral blood lymphocytes that correlate with transplant immunosuppression as welt as with acute rejection. Using statistical analysis of individual gene expression signals followed by hierarchical clustering and class prediction analysis we can demonstrate significant differences in the gene profiles of biopsies and PBL that define these clinical groups. Our first Specific Aim is to determine the gene expression profiles in transplant biopsies and PBL of patients in 3 well-established clinical classes. Successful completion of this Aim will create a comprehensive, statistically robust data set for gene expression profiles of both transplant biopsies and PBL including many presently unknown genes that can be correlated with clinical events following kidney transplantation. Our second Specific Aim is to establish the patterns for individual gene expression correlated with clinical events and outcomes. Successful completion of this Aim will define candidate gene sets that can be integrated with the parallel studies ofproteomics and complex trait genetics . We will use in silica tools to identify gene functions and connections that reveal novel pathways in transplant biology particularly the response of the donor kidney to transplantation in the context of tissue injury, repair and chronic allograft nephropathy.

尽管最近急性排斥的发生率降低了，慢性同种异体移植肾病和 免疫抑制药物副作用仍然是移植物丧失和患者发病率的主要原因。在这种情况下，必须提高我们对免疫反应的理解以及移植器官对免疫和非免疫损伤机制的反应。基因表达的分析是鉴定与移植生物学有关的分子途径的一种手段。项目1的目的是使用高密度微阵列技术来测量具有明确定义明确表型的患者的肾脏活检和外周血中的差异基因表达：急性排斥，慢性同种异体移植肾病和患者在12至24个月的良好方案中生存的患者。 - 功能肾脏移植。我们的初步 基于对近100名受试者的研究的数据表明，在活检和外周血淋巴细胞中的特征基因表达谱，与移植免疫抑制相关的外周血淋巴细胞与急性排斥相关。使用单个基因表达信号的统计分析，然后进行分层聚类和类预测分析，我们可以证明活检和PBL的基因谱存在显着差异，这些基因谱和PBL定义了这些临床组。我们的第一个具体目的是确定3个良好公认的临床类别中移植活检和PBL的基因表达谱。成功完成 AIM将为移植活检和PBL的基因表达谱创建一个全面的，统计上强大的数据集，包括许多目前未知的基因，这些基因与肾移植后可以与临床事件相关。我们的第二个具体目的是建立与临床事件和结果相关的个体基因表达的模式。该目标的成功完成将定义可以与蛋白质组学和复杂性状遗传学的平行研究集成的候选基因集。我们将使用二氧化硅工具来识别基因功能和连接，这些基因功能和连接揭示了移植生物学中的新途径，尤其是在组织损伤，修复和慢性同种异体同种异体肾病的背景下，供体肾脏对移植的反应。