Integrated spatial interrogation of cellular and molecular signatures of human kidney disease

人类肾脏疾病细胞和分子特征的综合空间询问

• 批准号: 10505776
• 负责人: Tarek Maurice Ashkar
• 金额: $ 93.18万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 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 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10505776
• 关键词: 3-Dimensional; Acute; Acute Renal Failure with Renal Papillary Necrosis; Atlases; Biological Markers; Biopsy; Biopsy Specimen; Cell Communication; Cells; Cellular biology; Chronic Kidney Failure; Clinical; Core Biopsy; Cytometry; Detection; Development; Disease; Disease Progression; Endothelial Cells; Epithelial Cells; Equilibrium; Fibrosis; Genes; Genetic Transcription; Goals; Health; Health system; Heterogeneity; Histopathology; Human; Image; Immune; Immunofluorescence Immunologic; In Situ; Incidence; Individual; Infrastructure; Injury; Injury to Kidney; Kidney; Kidney Diseases; Knowledge; Link; Longitudinal cohort; Maps; Microscopy; Mission; Molecular; Molecular Disease; Molecular Profiling; Molecular Structure; Morphology; Neighborhoods; Nephrons; Organ; Outcome; Pathogenesis; Pathology; Pathway interactions; Pattern; Persons; Phase; Phenotype; Proteomics; Public Health; Quality of life; Research; Resources; Specimen; Stromal Cells; Structure; Technology; Testing; Text; Therapeutic Intervention; Tissues; Tumor-infiltrating immune cells; United States National Institutes of Health; Vision; Work; base; cell type; cohort; digital pathology; disease phenotype; experience; human disease; immune activation; improved; indexing; injury and repair; kidney biopsy; molecular phenotype; novel; novel marker; novel therapeutics; precision medicine; preclinical study; protein expression; proteomic signature; renal epithelium; targeted treatment; tool; transcriptomics

(PLEASE KEEP IN WORD, DO NOT PDF) Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. Abstract There is a fundamental gap in understanding the mechanisms that determine progression in human kidney disease. The long-term goal is to characterize key cellular and molecular pathways regulating progression of acute and chronic kidney diseases (AKI and CKD), to identify novel markers that assess disease progression, and to develop specific therapeutic interventions targeting these pathways. There is often heterogeneity in the pattern of kidney injury whereby various cell types and cell states are differentially distributed across focal regions of a biopsy specimen. Immune cell sub-populations are observed in these injury regions, suggesting robust cross-talk between infiltrating immune cells and the resident renal epithelial, endothelial, and stromal cells. Further, these regional molecular disease phenotypes often are not fully appreciated on standard histopathologic assessment. Therefore, there is a critical need to expand our efforts to comprehensively localize cell types and cell states in the kidney, sub-phenotype disease, uncover cell-cell interactions, and understand the cellular and molecular phenotypes underlying morphologic changes in the kidney. The overarching hypothesis of this proposal is that mechanisms of kidney disease can only be understood when the diversity of cellular and molecular phenotypes are interpreted in the spatial context of the individuals’ kidney. The central hypothesis will be tested using an integrated pipeline of spatially resolved imaging, transcriptomic, and proteomic technologies that will capture the features of kidney disease at the cell, regional, and organ levels. These technologies include large scale 3D microscopy and tissue cytometry (3DTC), spatial transcriptomics (ST), and CO-Detection by indEXing (CODEX) multiplexed immunofluorescence. Together, this analytical pipeline will facilitate mapping of injury distribution and effectively link with other KPMP technologies through the following aims: Specific Aim 1: Deploy a suite of KPMP-approved spatial technologies as a synchronized analytical pipeline to define the cellular components and molecular structure of each human kidney biopsy. Specific Aim 2: Integrate imaging, transcriptomic, and proteomic signatures from each biopsy specimen to generate a multi-component spatial map of cellular and molecular phenotypes. Specific Aim 3: Integrate our analytical pipeline across the KPMP, linking our spatially-anchored cellular and molecular phenotypes to other KPMP technologies, pathology, and clinical features. The proposed research is significant, because it is the next step in a continuum of research that is expected to identify critically needed biomarkers of disease progression, optimize preclinical studies, and develop specific and targeted therapeutic interventions in the vast clinical problem of AKI and CKD.

（请保持文字，不要PDF） 在此输入文本，它是应用程序的新摘要信息。此部分不得超过30行文本。 摘要 在理解决定人类肾脏疾病进展的机制方面存在根本性的差距。长期目标是表征调节急性和慢性肾脏疾病（阿基和CKD）进展的关键细胞和分子途径，以确定评估疾病进展的新标志物，并开发针对这些途径的特定治疗干预措施。肾损伤的模式通常存在异质性，由此各种细胞类型和细胞状态在活检标本的病灶区域中差异分布。在这些损伤区域中观察到免疫细胞亚群，表明浸润免疫细胞与常驻肾上皮细胞、内皮细胞和基质细胞之间存在强烈的串扰。此外，这些区域性分子疾病表型通常不能在标准组织病理学评估中得到充分认识。因此，迫切需要扩大我们的努力，以全面定位肾脏中的细胞类型和细胞状态，亚表型疾病，揭示细胞-细胞相互作用，并了解肾脏形态学变化背后的细胞和分子表型。该建议的总体假设是，只有在个体肾脏的空间背景下解释细胞和分子表型的多样性时，才能理解肾脏疾病的机制。中心假设将使用空间分辨成像、转录组学和蛋白质组学技术的集成管道进行测试，这些技术将在细胞、区域和器官水平上捕获肾脏疾病的特征。这些技术包括大规模3D显微镜和组织细胞术（3DTC），空间转录组学（ST）和CO检测indEXing（CODEX）多重免疫荧光。总的来说，这个分析管道将有助于绘制损伤分布图，并通过以下目标与其他KPMP技术有效地联系起来：具体目标1：部署一套KPMP批准的空间技术作为同步分析管道，以确定每个人类肾脏活检的细胞成分和分子结构。具体目标二：整合每个活检标本的成像、转录组学和蛋白质组学特征，生成细胞和分子表型的多组分空间图谱。具体目标3：将我们的分析管道整合到KPMP中，将我们的空间锚定细胞和分子表型与其他KPMP技术、病理学和临床特征联系起来。这项拟议的研究意义重大，因为它是一系列研究的下一步，预计将确定急需的疾病进展生物标志物，优化临床前研究，并在阿基和CKD的巨大临床问题中开发特异性和靶向治疗干预措施。