PREcision Medicine through IntErrogation of Rna in the kidnEy (PREMIERE)

通过肾脏 RNA 检测实现精准医学 (PREMIERE)

• 批准号: 9910974
• 负责人: Nir Hacohen
• 金额: $ 46.09万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9910974
• 关键词: 3-Dimensional; Acute Renal Failure with Renal Papillary Necrosis; Architecture; Atlases; Bioinformatics; Biological Markers; Biomedical Research; Biopsy; Cell Extracts; Cell Lineage; Cells; Chronic Kidney Failure; Clinical; Complex; Computer Simulation; Computing Methodologies; Data; Development; Dimensions; Disease; Disease Marker; Excretory function; Expression Profiling; Fluid Balance; Funding; Future; Gene Expression; Gene Expression Profile; Genetic Structures; Genetic Transcription; Goals; Health; Heterogeneity; Hormonal; In Situ; In Situ Hybridization; Individual; Institution; Interdisciplinary Study; Kidney; Kidney Diseases; Laboratories; Lead; Link; Maintenance; Maps; Methods; Molecular; Molecular Analysis; Molecular Disease; Molecular Structure; Nephrons; Pathogenesis; Pathway interactions; Patients; Phase; Phenotype; Process; RNA; Renal Tissue; Reproducibility; Research Personnel; Role; Science; Site; Sodium Chloride; Source; Stains; Structure; Taxonomy; Techniques; Technology; Therapeutic; Tissue Procurements; Tissues; Work; analysis pipeline; base; biomarker development; blood pressure regulation; cell type; clinical care; data mining; design; droplet sequencing; experience; genome-wide; human tissue; improved; kidney biopsy; kidney cell; kidney dysfunction; new therapeutic target; next generation; novel; precision medicine; response; scale up; single cell analysis; single-cell RNA sequencing; targeted treatment; therapy development; tool; transcriptome sequencing; transcriptomics; wasting

ABSTRACT The kidney has developed a complex, three-dimensional architecture to serve its key functions, including excretion of waste substances, maintenance of the internal balance for fluid and salt, blood pressure control, and hormonal function. Understanding the roles of the individual renal cell types in these processes in health and disease is critical to develop novel targeted therapies. Extensive studies lead by this investigative group and others have started to identify molecular disease mechanism in renal biopsy tissues and helped to develop novel disease markers and therapies. However, up to now these studies were limited using biopsy tissue homogenates, making it difficult to discern the specific pathways activated in cell types. The PREcision Medicine through IntErrogation of Rna in the kidnEy (PREMIERE) Network will bring investigators from three leading biomedical research institutions with diverse, complementary expertise together. Our team has an established track record in working jointly to develop state of the art approaches in molecular analysis of renal disease. We will set out to mine our existing compendium of thousands of gene expression profiles from renal biopsy tissues to extract single cell signatures using advanced data mining tools. In parallel we will develop technologies in our laboratories towards single cell analysis of renal tissues and scale them down so that they can work on single cells extracted from small renal biopsies. These single cell profiles will be linked to the disease states of the patients. Key signatures associated with specific cells and diseases will be extracted and localized in the three dimensional context of the kidney using specific RNA staining techniques in the first phase of the project. In the second phase, the analytical strategies will be scaled up so that single cell profiles from specific groups of patients can be obtained in a robust and reproducible manner. To this end the PREMIERE investigators will work closely with the tissue procurement sites and the Central Hub of the KPMP, using their 20 years of experience in team science, so that at the end of the first KPMP funding cycle novel, cell type specific treatment targets are identified fueling the therapeutic pipelines of the future.

摘要 肾脏已经发展出一种复杂的三维结构，以发挥其关键功能，包括 排泄废物，维持体内水盐平衡，血压 控制和荷尔蒙功能。了解单个肾细胞类型在这些过程中的作用 在健康和疾病中的作用对于开发新的靶向疗法至关重要。由此引发的广泛研究 研究小组和其他人已经开始在肾活检组织中鉴定分子疾病机制 并帮助开发新的疾病标志物和治疗方法。然而，到目前为止，这些研究 限制使用活检组织匀浆，使得难以辨别细胞中激活的特定途径， 类型 肾内RNA整合精准医学（PREMIERE）网络将带来 来自三家领先的生物医学研究机构的研究人员，他们拥有多样化的互补专业知识 一起我们的团队在共同开发最先进的方法方面有着良好的记录 肾脏疾病的分子分析。我们将着手挖掘我们现有的数千个 使用先进的数据从肾活检组织中提取单细胞特征的基因表达谱 采矿工具与此同时，我们将在实验室开发技术，以实现肾细胞单细胞分析。 然后将它们缩小，这样他们就可以从小的肾活检中提取单细胞。 这些单细胞谱将与患者的疾病状态相关联。关联的密钥签名 特定的细胞和疾病将被提取并定位在肾脏的三维环境中 在项目的第一阶段使用特定的RNA染色技术。在第二阶段，分析 将扩大策略，以便可以在一个特定的患者群体中获得单细胞谱。 鲁棒和可再现的方式。 为此，PREMIERE研究者将与组织采集研究中心和中央研究中心密切合作， KPMP的枢纽，利用他们20年的团队科学经验，使在第一个KPMP结束时， 资助周期新的，细胞类型特异性的治疗靶点被确定，为治疗管道提供动力， 未来