Project 3: Mapping the Evolution of Chronic Transplant Injury in the Context of CMV Infection

项目3：绘制巨细胞病毒感染背景下慢性移植损伤的演变图 摘要/摘要 在器官移植的情况下，CMV感染会导致炎症，并与慢性 同种异体移植中的排斥反应，这会加速同种异体移植物的丢失和移植失败。连续不断的 在巨细胞病毒感染的背景下引发移植物炎症的分子机制尚不清楚。 器官背景下CMV感染和疾病的全基因组、蛋白质组和免疫组谱 移植可以产生一个全面的全球数据库来了解CMV感染和重新激活 并帮助设计新的策略来防止病毒重新激活和抑制抗- 供者豁免权。在项目3中，我们建议研究推动急性白血病的免疫反应的进化。 肾移植受者排斥反应、慢性排斥反应和CMV病毒感染的系列评估 移植物转录紊乱(AIM 1)、外周血T细胞和B细胞受体的克隆性增殖(TCR和 通过Next基因表达测序(NGS)，以及对重新激活的体液反应的变化 通过高通量抗体分析确定抗原表位(目标2)。此外，我们建议生成 通过测量供体来源细胞的变化无创监测慢性移植物损伤的生物标志物 DNA(dd-cfDNA)通过大规模多重聚合酶链式反应(mm-PCR)和高度精炼的基因集(kSORT和ucrm) 从以前的高通量微阵列研究中挖掘(目标3)。我们建议使用一组肾脏 来自美国最大的两个多器官移植项目(加州大学旧金山分校和加州大学洛杉矶分校)的移植患者。

PROJECT 3: Mapping the Evolution of Chronic Transplant Injury in the Context of CMV Infection SUMMARY/ABSTRACT CMV infection drives inflammation in the context of organ transplantation, and is associated with chronic rejection in the allograft, which drives accelerated allograft loss and transplant failure. The cascade of molecular mechanisms that trigger graft inflammation in the context of CMV infection are poorly understood. Whole genome, proteome, and immunome profiling of CMV infection and disease in the context of organ transplantation can generate a comprehensive global database to understand CMV infection and reactivation in an immunocompromised host and help design novel strategies to prevent viral reactivation and dampen anti- donor immunity. In Project 3, we propose to study the evolution of immune responses that drive acute rejection, chronic rejection, and CMV virus infection in kidney transplant recipients by serial assessments of graft transcriptional perturbations (Aim 1), clonal expansion of peripheral T cell and B cell receptors (TCRs and BCRs) through next gene expression sequencing (NGS), and variations in humoral responses to reactivation of antigenic epitopes by high-throughput antibody profiling (Aim 2). In addition, we propose to generate biomarkers for non-invasive monitoring of chronic graft injury by measuring changes in donor derived cell free DNA (dd-cfDNA) by massively multiplexed PCR (mmPCR) and highly refined gene-sets (kSORT and uCRM) mined from previous high-throughput microarray studies (Aim 3). We propose to use a cohort of kidney transplant patients from two of the largest multi-organ transplant programs in the US (UCSF and UCLA).