GENOMICS FOR KIDNEY TRANSPLANTATION

肾移植基因组学

• 批准号: 8171291
• 负责人: Daniel R. Salomon
• 金额: $ 0.08万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8171291
• 关键词: Actins; Acute-Phase Reaction; Apoptosis; Atrophic; Biopsy; Cells; Chronic; Classical Complement Pathway; Computer Retrieval of Information on Scientific Projects Database; Cytoskeleton; Data; Disease; Drug toxicity; Failure; Fibrosis; Funding; Genomics; Grant; Histologic; Immune; Immune response; Inflammation; Inflammatory; Injury; Institution; Kidney; Kidney Transplantation; Maps; Molecular; Molecular Profiling; Pathway interactions; Population; Prevention strategy; Process; Proteins; Proteomics; Research; Research Personnel; Resources; Set protein; Severities; Signal Transduction; Source; Tissues; Transplantation; Tubular formation; United States National Institutes of Health; Validation; effective therapy; genome-wide; insight; interstitial; protein expression; tandem mass spectrometry

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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 肾移植失败的最常见原因是组织病理学实体间质纤维化和肾小管萎缩（IFTA）的特征不明确。没有已知的统一机制，没有有效的治疗方法，也没有行之有效的预防策略。可能的机制包括慢性免疫排斥、炎症、药物毒性和继发因素造成的慢性肾损伤。为了获得进一步的机制了解，我们对不同严重程度的 IFTA 肾移植活检进行了大规模蛋白质组学研究。我们使用串联质谱法获取蛋白质组数据，并随后进行定量、差异蛋白质表达分析、验证和已知分子网络的功能注释。我们并行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至中度和重度疾病活检的进展。多组蛋白质被映射到不同的功能途径，其中许多蛋白质随着组织学严重程度而增加，包括与慢性排斥假说一致的免疫反应、炎症细胞激活和细胞凋亡。两个例子包括广泛的替代途径而不是经典的补体途径（以前没有被 IFTA 所重视），以及肌动蛋白细胞骨架和急性期反应的细胞信号传导的综合控制网络。总之，这种使用肾组织的蛋白质组学研究有助于深入了解与 IFTA 相关的几个生物学过程。