Genomics

在这次竞争性更新中，项目#1的3个目标保持不变：基因组生物标志物和具有直接临床和转化意义的生物发现的平衡。但在过去的6年里，基因组学领域发生了巨大的变化，我们带来了一整套新的下一代技术，以实现这些目标，为新时期的资金要求。我们也有显着 扩大了我们的科学团队，包括血浆蛋白质组学和心脏移植（项目#4）和多参数流式细胞术基因组学的新技术平台（核心B）。最后，我们将使用我们新的一套基因组工具和这一精心设计和互补的科学项目，以解决几个新的临床挑战，肾移植，已经演变在这最后一个时期： 移植后的脱敏和AMR，慢性排斥的变化模式，迫切需要了解当前的免疫抑制如何工作和失败，移植后心血管疾病的风险增加，以及慢性排斥和心脏病是由一组常见的，统一的免疫/炎症机制驱动的新假设。 具体目标1：使用新一代基因组技术发现与肾移植的发展、调节和结局相关的生物标志物特征和分子途径免疫研究300名肾移植患者的免疫进化。具体目标#2：应用全血、全基因组基因表达谱分析来发现基于基因表达的生物标志物特征， 对120例移植前HLA供者抗原特异性抗体阳性的患者进行脱敏治疗和移植，观察其急性和慢性抗体介导的排斥反应（AMR）。具体目标#3：通过应用最新的基因组分析技术，推进我们对慢性肾移植排斥反应机制的理解，详见具体目标#1。具体目标#4：开发新的基因组策略，以绘制移植后发育过程中驱动T和B细胞活化的主分子网络 免疫反应包括免疫抑制药物对激活诱导网络的影响。

In this competitive renewal, the 3 over-arching objectives of Project #1 remain the same: a balance of genomic biomarker and biological discovery with direct clinical and translational significance. But In the last 6 years, the field of genomics has changed dramatically and we bring a whole new suite of next generation technologies to bear on these objectives for the new period of funding requested. We have also significantly expanded our scientific team to Include plasma proteomics and heart transplantation (Project #4) and a novel technology platform for multi-parameter flow cytometry genomics (Core B). Finally, we will use our new suite of genomic tools and this carefully crafted and complementary set of scientific Projects to address several new clinical challenges for kidney transplantation that have evolved In this last period: HLA-antibody desensitization and AMR post-transplant, the changing paradigms of chronic rejection, the pressing need to understand how current immunosuppression works and fails, the Increased risks of cardiovascular disease post-transplant and the novel hypothesis that chronic rejection and heart disease are driven by a set of common, unifying mechanisms of immunity/inflammation. Specific Aim #1: Use a new generation of genomic technologies to discover biomarker signatures and molecular pathways involved in the development, regulation and outcomes of kidney transplantation Immunity to study the evolution of immunity In 300 kidney transplant patients. Specific Aim #2: Apply whole blood, genome-wide gene expression profiling to discover gene expression-based biomarker signatures for acute and chronic antibody-mediated rejection (AMR) in 120 patients with pre-transplant HLA donor antigen-specific antibodies undergoing desensitizafion and transplantation. Specific Aim #3: Advance our mechanistic understanding of chronic kidney transplant rejection by applying the latest genomic profiling technologies detailed In Specific Aim #1. Specific Aim #4: Develop new genomic strategies to map the master molecular networks driving T and B cell activation during the development of the post-transplant immune response Including the impact of Immunosuppressive drugs on activation-induced networks.