Genomics

基因组学

• 批准号: 8896392
• 负责人: John R Yates III
• 金额: $ 77.78万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8896392
• 关键词: Acute; Address; Alternative Splicing; Anemia; Antibodies; Antigens; Automobile Driving; B-Cell Activation; Biological; Biological Markers; Biopsy; Blood; Blood Cells; Blood Vessels; Cardiac; Cardiovascular system; Cause of Death; Cells; Chronic; Clinical; Clinical Research; Complement; DNA Sequence; Development; Diagnostic; Equilibrium; Event; Evolution; Failure; Flow Cytometry; Functional disorder; Funding; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Generations; Genetic; Genome; Genomic approach; Genomics; Graft Rejection; Graft Survival; Grant; Heart Diseases; Heart Transplantation; Immune; Immune response; Immunity; Immunosuppression; Immunosuppressive Agents; Inflammation; Inflammatory; Injury; Kidney Transplantation; Maps; Mass Spectrum Analysis; Mediating; MicroRNAs; Molecular; Molecular Profiling; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Plasma; Practice Management; Proteomics; Protocols documentation; Regulation; Regulatory Pathway; Renal function; Risk; Sampling; Science; Signal Transduction; Survival Rate; T-Lymphocyte; Technology; Testing; Time; Translating; Transplant Recipients; Transplantation; Ursidae Family; Whole Blood; Work; base; cardiovascular disorder risk; cardiovascular risk factor; clinical application; clinical practice; desensitization; design; epigenetic profiling; gene discovery; genome wide association study; genome-wide; genomic tools; graft function; high risk; immunosuppressed; interstitial; mRNA Expression; new technology; next generation; next generation sequencing; novel; peripheral blood; post-transplant disease; programs; response; tool; transcription factor

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.

在这一竞争性更新中，项目#1 的 3 个总体目标保持不变：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之间的平衡。但在过去 6 年里，基因组学领域发生了巨大变化，我们带来了一套全新的下一代技术，以实现新时期资金需求的这些目标。我们还显着地 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）以及用于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基因组工具套件和这套精心设计且互补的科学项目来解决肾移植的几个新的临床挑战，这些挑战在上一个时期已经发展起来：HLA-抗体 移植后脱敏和 AMR、慢性排斥反应范式的变化、迫切需要了解当前免疫抑制如何发挥作用和失败、移植后心血管疾病风险增加以及慢性排斥和心脏病是由一组因素驱动的新假设常见的、统一的免疫/炎症机制。 具体目标#1：使用新一代基因组技术来发现参与肾移植免疫的发展、调节和结果的生物标志物特征和分子途径，以研究 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来发现基于基因表达的生物标志物特征 120 名接受脱敏和移植的移植前 HLA 供体抗原特异性抗体患者的急性和慢性抗体介导的排斥反应 (AMR)。具体目标#3：通过应用具体目标#1 中详述的最新基因组分析技术，增进我们对慢性肾移植排斥的机制理解。具体目标#4：开发新的基因组策略来绘制移植后发育过程中驱动 T 和 B 细胞激活的主分子网络 免疫反应包括免疫抑制药物对激活诱导网络的影响。