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

基本信息

批准号：
10705127
负责人：
Tarek Maurice Ashkar
金额：
$ 93.19万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
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/10705127
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 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 Recommendation Research Resources Specimen Stromal Cells Structure Technology Testing Text Therapeutic Intervention Tissues United States National Institutes of Health Vision Work cell type cohort digital pathology disease phenotype experience human disease immune activation immune cell infiltrate improved indexing kidney biopsy kidney cell molecular phenotype novel novel marker novel therapeutics precision medicine preclinical study protein expression proteomic signature repaired spatial integration targeted treatment tool transcriptomics

项目摘要

(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.

（请保持言语，不要PDF）在此处输入文本，这是您应用程序的新摘要信息。本节必须不超过30行文本。抽象的理解决定人类肾脏疾病进展的机制存在根本的差距。长期的目标是表征关键的细胞和分子途径，以减轻急性和慢性肾脏疾病（AKI和CKD）进展的键，以鉴定评估疾病进展的新标记，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，在这种模式中，各种细胞类型和细胞态在活检标本的焦点区域中分布不同。在这些损伤区域观察到免疫细胞亚群，表明浸润性细胞与居民肾上皮，内皮和基质细胞之间的牢固串扰。此外，这些区域分子疾病表型通常在标准的组织病理学评估上不完全理解。因此，至关重要的需要将我们的努力扩展到肾脏，亚表型疾病，发现细胞 - 细胞相互作用的总体，定位细胞类型和细胞状态，并了解肾脏形态变化的细胞和分子表型。该提议的总体假设是，只有在个体肾脏的空间环境中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。中央假设将使用空间分辨成像，转录组和蛋白质组学技术的集成管道进行测试，该管道将在细胞，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的3D显微镜和组织细胞仪（3DTC），空间转录组学（ST）以及通过索引（codex）多重免疫荧光进行共检测。总之，该分析管道将促进损伤分布的映射，并通过以下目的有效与其他毕马威技术的绘制：特定目的1：部署一套由毕spmp批准的空间技术，作为同步分析管道，以定义每个人类肾脏生物学的细胞组件和分子结构。特定目标2：整合每个活检标本的成像，转录组和蛋白质组学特征，以生成细胞和分子表型的多组分空间图。具体目标3：将我们在毕马威会计能局的分析管道整合在一起，将我们的空间锚定细胞和分子表型与其他毕马威（KPMP）技术，病理和临床特征联系起来。拟议的研究很重要，因为这是连续研究步骤的下一步，预计将确定疾病进展的急需的生物标志物，优化临床前研究，并在AKI和CKD的广泛临床问题中开发特定和有针对性的治疗干预措施。