The Role of Renal Interstitium in Kidney Development

肾间质在肾脏发育中的作用

• 批准号: 10316848
• 负责人: Thomas Joseph Carroll
• 金额: $ 72.64万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10316848
• 关键词: Ablation; Anatomy; Binding; Bioinformatics; Biological Assay; Biology; Cell Lineage; Cells; Cellular biology; Co-Immunoprecipitations; Complex; Data; Defect; Development; Distal; Duct (organ) structure; Endothelium; Enhancers; Epithelial; Fibroblasts; Gene Expression; Gene Expression Profile; Genes; Genetic Epistasis; Genetic Transcription; Heterogeneity; Histologic; In Situ Hybridization; Individual; Injury to Kidney; Kidney; Kidney Diseases; Knowledge; Ligands; Ligation; Location; Maintenance; Maps; Modeling; Molecular; Mus; Natural regeneration; Nature; Nephrons; Newborn Infant; Organ; Organoids; Pathway interactions; Pattern; Play; Population; Regulon; Renal Interstitial Cell; Research; Role; Signal Pathway; Signal Transduction; Testing; Tissue Engineering; Tissues; cell replacement therapy; cell type; gain of function; genome-wide; insight; interstitial; interstitial cell; mutant; nephrogenesis; notch protein; promoter; single cell analysis; single-cell RNA sequencing; transcription factor; transcriptome sequencing

Project Summary/Abstract The kidney is patterned along a cortical to medullary axis with specific segments of the nephron, collecting duct and vasculature all lying adjacent to each other in histologically distinct domains. In order for a kidney to function, different cell types from different cellular lineages must form at the same anatomical location. Although there has been some insight into how the individual lineages become patterned (such as proximal distal patterning of the nephron), how the different cell types/lineages coordinate their development resulting in the global patterning of the organ is unknown. We have recently found that the renal interstitial cells show extensive heterogeneity and patterning along the cortical/medullary axis of a newborn mouse kidney[1]. The patterned domains of the renal interstitium precisely map to the different anatomical domains within the kidney. How the different interstitial cell types arise and what role they play in kidney development/function are unknown. We hypothesize that the interstitium functions to relay and integrate signals from the different lineages and in turn, reinfources and integrates the differentiation of the renal parenchyma along the cortical/ medullary axis. Using bioinformatic analysis of single cell RNA-Seq data, we have identified unique transcriptional signatures for the different interstitial cell types. This information will allow us to understand how the pattern is established as well as its function. In this proposal, we will focus on the specification and function of a sub-population of interstitial cells we will refer to as the proximal tubule (PT) interstitium. In this proposal, we will investigate the mechanisms underlying specification of a subpopulation of renal fibroblasts we refer to as the proximal tubules interstitium (PT interstitium). Notch/Rbpj and Yap/Taz transcription factors are both active within this population and ablation of either pathway using Foxd1Cre has revealed overlapping roles in the specification of this cell type. Our preliminary analysis indicates that the PT interstitium is necessary for the maturation of the adjacent proximal tubules. We hypothesize that the PTs and/or endothelia produce Notch/Rbpj and Yap/Taz activators and that cells with overlapping pathway activation become PT intersitium. The PT interstitium produces signals that promote the differentiation/maturation of the PTs. This crosstalk allows the co-maturation and integration of the proximal tubules and other cortical cell types. We further hypothesize that disruption of normal cortical-medullary pattern in renal organoids leads to defects in Yap/Taz and/or Notch/Rbpj signaling and contributes to the lack of nephron maturation in these tissues. These hypotheses will be tested here. Completion of these aims will open up an entirely new field of kidney interstitial biology that will have a long and lasting impact on the multiple fields including kidney development, kidney disease, tissue engineering and kidney injury/regeneration.

项目摘要/摘要 肾脏沿着皮质至髓质轴形成图案 收集管道和脉管系统都在组织学不同的领域相邻。为了 肾脏到功能，不同细胞谱系的不同细胞类型必须在相同的解剖学下形成 地点。尽管人们对单个谱系如何变形有所了解（例如 肾单位的近端远端图案），不同的细胞类型/谱系如何协调其发育 导致器官的全球模式尚不清楚。 我们最近发现，肾脏间质细胞显示出广泛的异质性和图案 沿着新生小鼠肾脏的皮质/髓质轴[1]。肾脏间质的图案域 精确地映射到肾脏内的不同解剖域。不同的间质细胞类型如何 出现以及它们在肾脏发育/功能中的作用尚不清楚。我们假设 间质功能以中继和整合来自不同谱系的信号，然后再载入 并整合沿皮质/髓质轴的肾实质的分化。使用 单细胞RNA-seq数据的生物信息学分析，我们已经确定了独特的转录特征 不同的间质细胞类型。这些信息将使我们能够了解如何建立模式 作为其功能。在此提案中，我们将重点介绍间质亚群的规范和功能 我们将称为近端小管（PT）间质的细胞。 在此提案中，我们将研究肾脏亚群的基础机制 成纤维细胞我们称为近端小管间质（PT间质）。 Notch/RBPJ和YAP/TAZ 转录因子在此人群中都活跃，并且使用FOXD1CRE的两种途径的消融 在该单元格的规范中揭示了重叠的角色。我们的初步分析表明PT 间质是相邻近端小管的成熟所必需的。我们假设PTS 和/或内皮产生Notch/RBPJ和YAP/TAZ激活剂，并且具有重叠途径的细胞 激活成为PT互质。 PT间质产生的信号可以促进 PT的分化/成熟。该串扰允许近端共同成熟和整合 小管和其他皮质细胞类型。我们进一步假设正常皮质中性模式的破坏 在肾脏器官中，导致YAP/TAZ和/或Notch/RBPJ信号的缺陷，并导致缺乏 这些组织中的肾单位成熟。这些假设将在这里进行检验。这些目标的完成将开放 建立一个全新的肾脏间质生物学领域，将对多个多元化产生较长而持久的影响 包括肾脏发育，肾脏疾病，组织工程和肾脏损伤/再生在内的领域。