Genomics

在这次竞争性更新中，项目#1的3个总体目标保持不变：平衡基因组生物标记物和具有直接临床和翻译意义的生物学发现。但在过去的6年里，基因组学领域发生了巨大的变化，我们带来了一套全新的下一代技术来实现这些目标，以满足新的资金要求。我们还显著地 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)和多参数流式细胞仪基因组学的新技术平台(核心B)。最后，我们将使用我们的新的基因组工具和这套精心设计的和互补的科学项目来解决肾移植在最后阶段进化出的几个新的临床挑战：人类白细胞抗原抗体。 这些问题包括：移植后的脱敏和AMR、慢性排斥反应范式的变化、了解当前免疫抑制的作用和失败的迫切需要、移植后心血管疾病风险的增加以及慢性排斥反应和心脏病是由一套共同的、统一的免疫/炎症机制驱动的新假说。 具体目标1：利用新一代基因组技术发现参与肾移植免疫发展、调节和结局的生物标志物和分子途径，研究300例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来发现基于基因表达的生物标记物签名 120例移植前人类白细胞抗原供体特异性抗体阳性患者接受脱敏和移植后的急、慢性抗体介导的排斥反应。具体目标3：通过应用具体目标1中详述的最新基因组图谱技术，提高我们对慢性肾移植排斥反应的机制的理解。具体目标4：开发新的基因组策略，绘制在移植后发育过程中驱动T和B细胞活化的主要分子网络 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.