Genomics for Kidney Transplantation

描述（由申请人提供）：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）的开发技术的应用，以促进我们对肾移植的临床问题和移植基础生物学的理解。我们的观点是，这是肾移植的系统生物学方法。这些努力得到了一组在所有三个科学领域以及临床肾移植和生物信息学和统计学方面具有专业知识的合作者的支持。 我们将生成的数据类型将分为两类：诊断和发现。诊断组分将由潜在复杂的基因和蛋白质表达特征组成，其将与特定临床事件（如急性排斥、慢性同种异体移植物肾病和长期功能良好的移植物而无排斥）具有统计学上有效的相关性。发现部分将包括在这些复杂的基因组特征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和肾移植活检中鉴定与活检证实的急性排斥和慢性同种异体移植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参与宿主免疫应答和供体器官对移植的应答的分子途径的了解，和3）免疫抑制的充分性，如通过不存在排斥相关基因和蛋白质表达所定义的，可以通过基因和蛋白质表达谱来确定。我们还建议研究种族和性别至少会影响移植后表达的一部分基因转录本和蛋白质，并与结果相关的可能性。 本申请的第一个目标是将基因表达谱数据与蛋白质组学（项目2）和复杂性状遗传学（项目3）产生的数据并行整合，以促进对临床肾移植分子基础的更全面理解。第二个是建立必要的原则证据，设计一个前瞻性的临床试验，以测试的假设，PBL配置文件可以用来监测免疫抑制的疗效在“实时”。

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'.