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.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 肾移植失败的最常见原因是组织病理学特征不佳的实体间质纤维化和肾小管萎缩（IFTA）。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引起的慢性肾损伤。为了获得更深入的机制见解，我们对不同严重程度IFTA的肾移植活检组织进行了大规模的蛋白基因组学研究。我们使用串联质谱法获得蛋白质组数据，随后进行定量，分析差异蛋白质表达，验证和已知分子网络的功能注释。我们进行了全基因组表达谱平行。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，许多增加与组织学的严重程度，包括免疫反应，炎症细胞活化，细胞凋亡与慢性排斥假说一致。两个例子包括广泛的人口的替代，而不是经典的补体途径，以前不赞赏IFTA，和一个全面的控制网络的肌动蛋白细胞骨架和细胞信号的急性期反应。总之，这种利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。