GENOMICS FOR KIDNEY TRANSPLANTATION

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 肾移植失败的最常见原因是组织病理学特征不佳的间质纤维化和肾小管萎缩(IFTA)。目前还没有已知的统一机制，没有有效的治疗方法，也没有经过验证的预防策略。可能的机制包括慢性免疫排斥、炎症、药物毒性和继发性因素造成的慢性肾脏损伤。为了获得进一步的机制认识，我们对不同严重程度的IFTA肾移植活检进行了大规模的蛋白质基因组学研究。我们使用串联质谱仪获得了蛋白质组数据，随后对已知的分子网络进行了量化、差异蛋白质表达分析、验证和功能注释。我们并行地进行了全基因组表达谱分析。超过1400种具有独特表达谱的蛋白质追踪了从正常移植活检到轻度到中度和重度疾病的活检的进展。多组蛋白质被映射到不同的功能通路，其中许多随着组织学严重程度的增加而增加，包括免疫反应、炎性细胞激活和与慢性排斥假设相一致的凋亡。两个例子包括广泛的替代途径而不是传统的补体途径，以前IFTA没有意识到这一点，以及急性时相反应的肌动蛋白细胞骨架和细胞信号的全面控制网络。综上所述，这种使用肾脏组织的蛋白质组学工作有助于从机械上洞察与IFTA相关的几个生物过程。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The most common cause of kidney transplant failure is the poorly characterized histopathologic entity interstitial fibrosis and tubular atrophy (IFTA). There are no known unifying mechanisms, no effective therapy, and no proven preventive strategies. Possible mechanisms include chronic immune rejection, inflammation, drug toxicity, and chronic kidney injury from secondary factors. To gain further mechanistic insight, we conducted a large-scale proteogenomic study of kidney transplant biopsies with IFTA of varying severity. We acquired proteomic data using tandem mass spectrometry with subsequent quantification, analysis of differential protein expression, validation, and functional annotations to known molecular networks. We performed genome-wide expression profiling in parallel. More than 1400 proteins with unique expression profiles traced the progression from normal transplant biopsies to biopsies with mild to moderate and severe disease. Multiple sets of proteins were mapped to different functional pathways, many increasing with histologic severity, including immune responses, inflammatory cell activation, and apoptosis consistent with the chronic rejection hypothesis. Two examples include the extensive population of the alternative rather than the classical complement pathway, previously not appreciated for IFTA, and a comprehensive control network for the actin cytoskeleton and cell signaling of the acute-phase response. In summary, this proteomic effort using kidney tissue contributes mechanistic insight into several biologic processes associated with IFTA.