Single cell multiomic and spatial atlas of acute and chronic kidney injury

急慢性肾损伤的单细胞多组学和空间图谱

基本信息

批准号：
10703444
负责人：
Sanjay Jain
金额：
$ 86.04万
依托单位：
WASHINGTON UNIVERSITY
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/10703444
关键词：
3-Dimensional ATAC-seq Acute Acute Renal Failure with Renal Papillary Necrosis Adult Atlases Automobile Driving Benchmarking Binding Bioinformatics Biological Biological Assay Biopsy Catalogs Cell Communication Cell Nucleus Cells Cellular biology Chromatin Chronic Chronic Kidney Failure Clinical Collaborations Complex Controlled Vocabulary Cytometry Data Data Set Development Diagnosis Diagnostic Disease Disease Outcome Endothelium Ensure Environment Epigenetic Process Ethnic Origin Evaluation Extracellular Matrix Fostering Freezing Gene Expression Gene Expression Regulation Genes Genetic Genomics Histologic Human Human BioMolecular Atlas Program Immune Infrastructure Injury Injury to Kidney Institution Joints Kidney Kidney Diseases Knowledge Measures Methods Modality Molecular Molecular Biology Molecular Profiling Neighborhoods Nephrology Nephrons Nerve Organ Participant Pathologic Pathology Patient Care Patients Phase Process Production Proteins Protocols documentation Publications Quality Control RNA Race Recommendation Regulation Reporting Research Personnel Resolution SNAP receptor Sampling Science Sex Differences Site Small Nuclear RNA Specimen Handling Stromal Cells Technology Text Tissue Embedding Tissue atlas Tissues Translational Research Transposase Tubular formation Urine Validation XCL1 gene biobank cell type clinical care data integration data sharing design epigenome epigenomics flexibility insight interstitial kidney biopsy kidney cell knowledge integration large scale data molecular phenotype multimodal data multimodality multiple omics nephrogenesis new technology novel patient oriented research precision medicine prognosis biomarker programs racial diversity sex single cell technology single nucleus RNA-sequencing single-cell RNA sequencing spatial relationship synergism therapeutic target tissue processing tongue papilla transcription factor transcriptome 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. Understanding kidney disease relies upon defining the complexity of cell types and states, their associated molecular profiles, and interactions within tissue neighborhoods. We pioneered the development of novel tissue processing methods in the KPMP that uses a limited amount of human kidney biopsy tissue for single nucleus (sn) omics and spatial technologies across institutions while allowing parallel histological evaluation. Using our TISAC-approved snRNA-seq assay on reference, AKI and CKD biopsies, we generated a snRNA atlas from 200K nuclei covering cortex to papilla and revealed 53 healthy and 47 altered cell states. These represent cycling, degenerative, adaptive/maladaptive and transitioning cells in tubular and interstitial compartments. We augmented these efforts by integrating these data with newer technologies that measure RNA and epigenome in the same nucleus and defined key transcription factors associated with gene expression changes in transition of healthy cell to altered cell states. In a collaborative effort in KPMP and HuBMAP, we integrated snRNA-seq, scRNA-seq, SNARE-seq2, two different spatial transcriptomic technologies and 3D cytometry. From this we were able to define biologically meaningful cell-cell interactions, cognate molecular interactions and genes associated with adaptive states that correlate with worse CKD outcomes. Deeper sampling and integrated analyses ensuring tissue economy of AKI and CKD biopsies is still needed to overcome gaps in clinicopathological-molecular determinants, and to assess effect of race, sex, ethnicity, clinical attributes, mechanisms of gene regulation, shifts in cell states, and characterization of biologically relevant niches. To this end we will use paired snRNA-seq and snATAC-seq (chromatin accessibility) to define mechanisms associated with altered state transitions, which will enable discovery of potential causative epigenetic factors driving RNA or protein changes in disease (Aim 1). To further define the spatial contexts of injury niches for biological insights, we will evaluate and implement highly multiplexed spatial transcriptomics technologies (Aim 2) and integrate knowledge from our transcriptomic and epigenomic atlas with other orthogonal technologies in the KPMP and other consortia (Aim 3). This collective effort will enable the creation of a high resolution spatial molecular atlas of healthy and diseased kidneys that can be used as a benchmark to interrogate and interpret molecular information in a single patient’s biopsy that can inform clinical care.

（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。理解肾脏疾病依赖于定义细胞类型和状态的复杂性，它们的相关分子谱以及组织社区内的相互作用。我们开创了KPMP中新型组织加工方法的开发，该方法使用有限量的人类肾脏活检组织来进行单个核（SN）的OMICS和空间技术，同时允许并行组织学评估。使用我们的TISAC批准的SNRNA-SEQ分析，AKI和CKD活检，我们从200K核覆盖皮质的200K核覆盖皮质到乳头的核中产生了一个SnRNA地图集，并揭示了53个健康和47个改变的细胞状态。这些代表了管状和间质室中的循环，退化，自适应/适应性和过渡细胞。我们通过将这些数据与较新的技术相结合，从而在相同的核和定义的关键转录因子中衡量与基因表达变化在健康细胞向改变细胞状态的转变时相关的关键转录因子的较新技术来增强这些努力。在KPMP和HubMap的协作工作中，我们集成了SNRNA-SEQ，SCRNA-SEQ，SNARE-SEQ2，两种不同的空间转录组技术和3D细胞仪。由此，我们能够定义具有生物学上有意义的细胞 - 细胞相互作用，同源分子相互作用以及与与CKD结果较差的适应性状态相关的基因。仍然需要更深入的采样和集成分析，以确保AKI和CKD活检的组织经济，以克服临床分子确定剂的差距，并评估种族，性别，种族，临床属性，基因调节机制的影响，细胞状态的转移机制，细胞状态和生物学上相关的NICHES的特征。为此，我们将使用成对的SNRNA-SEQ和SNATAC-SEQ（染色质访问性）来定义与状态转变改变相关的机制，这将使能够发现驱动RNA或蛋白质变化的潜在致病表观遗传因子（AIM 1）。为了进一步定义生物学见解的损伤壁ches的空间环境，我们将评估和实施高度多重的空间转录组技术（AIM 2），以及来自我们的转录组和表观基因组学地图集的综合知识与KPMP和其他Consoria和其他Consoria和其他Consortia（AIM 3）。这项集体努力将使您可以在健康和解散的肾脏的高分辨率空间分子图中创建，这些空间分子可以用作单个患者的活检中询问和解释可以为临床护理提供咨询的基准。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Computational Pathology Fusing Spatial Technologies.

融合空间技术的计算病理学。

DOI：
10.2215/cjn.0000000000000146
发表时间：
2023
期刊：
Clinical journal of the American Society of Nephrology : CJASN
影响因子：
0
作者：
Border,Samuel;Lucarelli,Nicholas;Eadon,MichaelT;El-Achkar,TarekM;Jain,Sanjay;Sarder,Pinaki
通讯作者：
Sarder,Pinaki