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Single-cell analysis to promote kidney repair

单细胞分析促进肾脏修复

基本信息

批准号：
10646473
负责人：
BENJAMIN D. HUMPHREYS
金额：
$ 73.22万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10646473
关键词：
3-Dimensional Ablation Acute Acute Renal Failure with Renal Papillary Necrosis Adopted Atlases Attenuated Automobile Driving Bioinformatics California Candidate Disease Gene Cell Nucleus Cells Chromatin Chronic Disease Chronic Kidney Failure Communities Data Data Set Databases Development Diagnosis Epigenetic Process Epithelial Cells Excision Female Fibrosis Gene Deletion Gene Expression Genes Genetic Genetic Transcription Hospitalization Human Immunohistochemistry Impairment In Situ Hybridization Inflammation Inflammatory Injury Injury to Kidney Intervention Kidney Kidney Diseases Knock-out Knowledge Laboratories Logic MAP4K4 gene Maps Medicare Modeling Modification Molecular Mus NF-kappa B Nephrons Nuclear Nuclear RNA Online Systems Outcome Pathway interactions Patient-Focused Outcomes Patients Persons Population Predisposition Probability Process Profibrotic signal Property Recovery Recurrence Regulator Genes Renal function Renal tubule structure Research Resources Risk Role Route Sampling Sex Differences Signal Transduction Surveys TNF Receptor-Associated Factors Technology Testing Therapeutic Intervention Time Transgenic Mice Tubular formation Universities Visualization software Washington adverse outcome aged cell type data mining epigenome epithelial injury experience genetic approach high risk improved improved outcome injured kidney biopsy kidney repair male member men mouse model multimodal data multimodality multiple omics novel novel strategies novel therapeutic intervention prevent profibrotic cytokine repair strategy repaired response response to injury sex single cell analysis single molecule single nucleus RNA-sequencing single-cell RNA sequencing therapeutic development therapeutic target transcriptome transcriptome sequencing transcriptomics

项目摘要

Summary Acute kidney injury (AKI) has a wide spectrum of outcomes from recovery to a long-term transition to chronic kidney disease (CKD). Between 2000 and 2014, AKI hospitalizations have increased from 3.5 to 11.7 per 1000 persons. Medicare patients aged 66 years and older hospitalized for AKI have a 35% cumulative probability of a recurrent AKI hospitalization within one year and 28% will be diagnosed with CKD in the same time frame. Men have a higher risk of AKI, and of developing progressive CKD, although the mechanisms are poorly understood. In the mouse, males also show a heightened vulnerability to AKI. Recent single cell RNA-seq studies from the McMahon and Kim groups have highlighted marked differences in gene expression between the sexes in proximal tubule segments, the region of the nephron most susceptible to AKI. Preliminary studies in the Humphreys and McMahon laboratories using single nuclear sequencing identified a cell type resulting from failed repair of proximal tubule cells (FR-PTC) following mild to severe AKI with a pro-inflammatory, pro- fibrotic signature. FR-PTCs are hypothesized to drive progressive kidney disease following AKI. This proposal centers on the postulates that an understanding of sex differences in response to AKI, and the application of genetic approaches to target proinflammatory properties of FR-PTCs and to eliminate FR-PTCs following renal repair, will be effective routes to ultimately benefit patient outcomes post AKI. To this end, we have assembled a complementary team, with prior collaborative experience: Humphreys (Washington University), Kim (University of Pennsylvannia) and McMahon (University of Southern California). All team members have participated in the ReBuilding a Kidney Consortium. In Specific Aim 1: we will characterize successful versus failed proximal tubule repair with single nucleus transcriptomics (snRNA-seq) and single nuclear chromatin accessibility studies (scATAC-seq) in male and female mouse models examining key findings in human kidney biopsies. In Specific Aim 2: we will harmonize multimodal datasets generated in Specific Aim1 to facilitate viewing and interrogation of these data by the broad research community. Mining of these data by the group will focus on defining the regulatory logic of repair strategies and outcomes in the male and female kidney. In Specific Aim 3: we will examine the hypothesis that adverse outcomes in the male kidney following AKI are driven by NF-kB pathway components Nfkb1 and TNIK in FR-PTCs, genetically eliminating the action of these genes. We will generate and validate a new transgenic mouse resource for the community, enabling genetic modification and elimination of FR-PTCs. We will determine whether FR-PTC removal has a favorable outcome, as we predict, on progressive kidney disease following AKI.

摘要急性肾损伤(AKI)具有从恢复到长期向慢性过渡的广泛结局肾病(CKD)。2000至2014年间，AKI的住院率从每1000人3.5人增加到11.7人人。66岁及以上因AKI住院的联邦医疗保险患者有35%的累积概率在一年内再次住院的AKI患者中，28%的患者将在同一时间段内被诊断为慢性肾脏病。男性患AKI和进展的CKD的风险更高，尽管这种机制很差明白了。在老鼠身上，雄性也表现出对AKI的高度易感性。最近的单细胞RNA-SEQ 麦克马洪和金氏研究小组的研究强调了两个组织在基因表达上的显著差异近端肾小管段是肾单位最易发生AKI的区域。初步研究在Humphreys和McMahon实验室中，使用单核序列确定了一种细胞类型，结果是从近端小管细胞修复失败的近端小管细胞(FR-PTC)，在轻到重度AKI后，用促炎，亲- 纤维性征兆。FR-PTCs被认为是AKI后导致进展性肾脏疾病的原因。这项建议集中在对AKI反应的性别差异的理解和应用的假设靶向FR-PTCs致炎特性和消除肾后FR-PTCs的遗传学方法修复，将是最终受益于AKI后患者预后的有效途径。为此，我们齐聚一堂一个互补的团队，有过合作经验：Humphreys(华盛顿大学)，Kim (宾夕法尼亚大学)和麦克马洪(南加州大学)。所有团队成员都有参与了肾财团的重建。具体目标1：我们将比较成功与单核转录组和单核染色质近端小管修复失败雄性和雌性小鼠模型的可及性研究(scatac-seq)检查人类肾脏的关键发现活组织检查。在具体目标2：我们将协调在特定Aim1中生成的多模式数据集，以促进广泛的研究界对这些数据的查看和询问。该小组对这些数据的挖掘将侧重于确定男性和女性肾脏修复策略和结果的调节逻辑。在……里面具体目标3：我们将检验AKI后男性肾脏不良后果的假设在FR-PTCs中由NF-kB通路成分Nfkb1和Tnik驱动，从基因上消除这些作用基因。我们将为社区生成并验证新的转基因小鼠资源，使基因 FR-PTCs的修饰和消除。我们将确定去除FR-PTC是否有有利的正如我们预测的那样，AKI后进展性肾脏疾病的结局。