Genomics for Kidney Transplantation

肾移植基因组学

• 批准号: 7918722
• 负责人: Daniel R. Salomon
• 金额: $ 74.43万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-12 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7918722
• 关键词: Genomics; Kidney; Transplantation

DESCRIPTION (provided by applicant): The theme of this Program Project is to test the application of developing technologies for gene expression profiling (Project 1), proteomics (Project 2) and complex trait genetics (Project 3) to advance our understanding of kidney transplantation in the context of both its clinical problems and the basic biology of transplantation. Our view is that this is a systems biology approach to kidney transplantation. These efforts are supported by a group of collaborators with expertise in all three scientific areas as well as expertise in clinical kidney transplantation and bioinformatics and statistics. The kind of data we will generate will be of two kinds: diagnostic and discovery. The diagnostic component will consist of potentially complex gene and protein expression signatures that will have statistically valid correlations to specific clinical events like acute rejection, chronic allograft nephropathy and long term well-functioning transplants with no rejection. The discovery component will consist of identifying within these complex genomic signatures, specific gene candidates that correlate with transplant events and outcomes. Our hypotheses are: 1) that gene and protein expression signatures can be identified in PBL and kidney transplant biopsies that correlate with biopsy-proven acute rejection and chronic allograft nephropathy, 2) that gene and protein expression profiles provide insights into the molecular pathways involved in both the host immune response and the donor organ's response to transplantation, and 3) that the adequacy of immunosuppression, as defined by the absence of rejection-related gene and protein expression, can be determined by the gene and protein expression profiles. We also propose to examine the possibility that race and sex will influence at least a subset of gene transcripts and proteins expressed post transplant and correlate with outcomes. The first objective of this application will be to integrate data on gene expression profiling in parallel with data generated by proteomics (Project 2) and complex trait genetics (Project 3) to advance a more comprehensive understanding of the molecular basis of clinical kidney transplantation. The second is to establish the requisite proof of principle to design a prospective clinical trial to test the hypothesis that PBL profiles can be used to monitor the efficacy of immunosuppression in 'real-time'.

描述(申请人提供)：本计划项目的主题是测试基因表达谱(项目1)、蛋白质组学(项目2)和复杂性状遗传学(项目3)开发技术的应用，以促进我们从肾移植的临床问题和移植的基本生物学的背景下理解肾移植。我们的观点是，这是肾脏移植的系统生物学方法。这些努力得到了一组合作者的支持，这些合作者在所有三个科学领域都有专长，并且在临床肾移植、生物信息学和统计学方面也有专长。 我们将生成两种类型的数据：诊断和发现。诊断部分将包括潜在的复杂基因和蛋白质表达特征，这些特征将在统计上有效地与特定的临床事件相关，如急性排斥反应、慢性同种异体移植肾病和长期功能良好的无排斥移植。发现部分将包括在这些复杂的基因组签名中识别与移植事件和结果相关的特定候选基因。我们的假设是：1)可以在PBL和肾移植活检组织中识别与活检证实的急性排斥和慢性移植物肾病相关的基因和蛋白质表达特征，2)基因和蛋白质表达谱提供了对宿主免疫反应和供体器官对移植的反应所涉及的分子途径的洞察，以及3)免疫抑制的充分性，如缺乏排斥相关基因和蛋白质表达的定义，可以由基因和蛋白质表达谱确定。我们还建议检查种族和性别是否会影响移植后表达的基因转录本和蛋白质的至少一个子集，并与结果相关。 这项应用的第一个目标将是将基因表达谱数据与蛋白质组学(项目2)和复杂特征遗传学(项目3)产生的数据相结合，以促进对临床肾移植的分子基础的更全面的理解。第二是建立必要的原则性证据，以设计一项前瞻性临床试验，以检验PBL图谱可用于‘实时’监测免疫抑制疗效的假设。