The Role of Renal Interstitium in Kidney Development

肾间质在肾脏发育中的作用

• 批准号: 10621859
• 负责人: Thomas Joseph Carroll
• 金额: $ 69.77万
• 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/10621859
• 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; Epithelium; 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; Specific qualifier value; Testing; Tissue Engineering; Tissues; cell cortex; cell replacement therapy; cell type; gain of function; genome-wide; insight; interstitial; interstitial cell; loss of function; 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.

项目概要/摘要 肾脏沿着皮质到髓质轴排列，具有肾单位的特定部分， 集合管和脉管系统在组织学上不同的区域中彼此相邻。为了一个 肾脏要发挥功能，来自不同细胞谱系的不同细胞类型必须在相同的解剖结构中形成 地点。尽管对于个体谱系如何形成模式已有一些见解（例如 肾单位的近端远端模式），不同的细胞类型/谱系如何协调它们的发育 导致该器官的整体模式尚不清楚。 我们最近发现肾间质细胞表现出广泛的异质性和模式 沿着新生小鼠肾脏的皮质/髓质轴[1]。肾间质的模式结构域 精确映射到肾脏内的不同解剖区域。不同的间质细胞类型如何 它们在肾脏发育/功能中发挥什么作用尚不清楚。我们假设 间质的功能是传递和整合来自不同谱系的信号，进而强化 并整合肾实质沿皮质/髓质轴的分化。使用 通过对单细胞 RNA-Seq 数据的生物信息分析，我们发现了独特的转录特征 不同的间质细胞类型。这些信息也将使我们能够了解模式是如何建立的 作为它的功能。在本提案中，我们将重点关注间隙子群的规范和功能 我们将其称为近端小管 (PT) 间质细胞。 在本提案中，我们将研究肾亚群规范的潜在机制 我们将成纤维细胞称为近端小管间质（PT 间质）。 Notch/Rbpj 和 Yap/Taz 转录因子在该群体中都很活跃，并且使用 Foxd1Cre 消除任一途径已 揭示了这种细胞类型规范中的重叠作用。我们的初步分析表明，PT 间质对于邻近近端小管的成熟是必需的。我们假设 PT 和/或内皮细胞产生Notch/Rbpj和Yap/Taz激活剂，并且具有重叠途径的细胞 活化成为PT间质。 PT 间质产生信号，促进 PT 的分化/成熟。这种串扰允许近端的共同成熟和整合 小管和其他皮质细胞类型。我们进一步假设正常皮质髓质模式的破坏 肾类器官中的缺陷导致 Yap/Taz 和/或 Notch/Rbpj 信号传导缺陷，并导致缺乏 肾单位在这些组织中成熟。这些假设将在这里得到检验。完成这些目标将开启 建立一个全新的肾间质生物学领域，将对多种疾病产生长期而持久的影响 领域包括肾脏发育、肾脏疾病、组织工程和肾脏损伤/再生。