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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此，可以在其他清晰的条目中表示。列出的机构是 对于中心，这不一定是调查员的机构。 肾移植衰竭的最常见原因是特征性较差的组织病理学实体间质性纤维化和管状萎缩（IFTA）。没有已知的统一机制，没有有效的疗法，也没有证明的预防策略。可能的机制包括慢性免疫排斥，炎症，药物毒性以及次要因素的慢性肾损伤。为了获得进一步的机械洞察力，我们对具有不同严重程度的IFTA进行了大规模的蛋白质组学研究。我们使用串联质谱法获得了蛋白质组学数据，并随后定量，分析差异蛋白表达，验证和对已知分子网络的功能注释。我们并行进行了全基因组表达分析。具有独特表达曲线的1400多种蛋白质将从正常移植活检到轻度至中度和重度疾病的活检的进展。将多组蛋白质映射到不同的功能途径，许多蛋白质随着组织学严重程度的增加，包括免疫反应，炎性细胞激活和与慢性排斥假设一致的凋亡。有两个例子包括替代方案的广泛人群，而不是经典的补体途径，以前对IFTA不欣赏，以及用于肌动蛋白细胞骨架的综合控制网络和急性相反应的细胞信号传导。总而言之，这种使用肾脏组织的蛋白质组学努力为与IFTA相关的几种生物过程提供了机械洞察力。