Cell Fate Regulation of Nephron Progenitors

肾单位祖细胞的细胞命运调控

• 批准号: 9185301
• 负责人: Joo-Seop Park
• 金额: $ 33.93万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9185301
• 关键词: Address; Affect; Binding Sites; Bioinformatics; Cell Differentiation process; Cell Fate Control; Cells; ChIP-seq; Collaborations; Complex; Consensus Sequence; Consumption; Coupled; DNA; Data; Defect; Development; Elements; Embryo; End stage renal failure; Equilibrium; Feedback; Gene Targeting; Genes; Genetic Transcription; Genomics; Goals; HOX protein; Homeobox Genes; Hypertension; Instruction; Intervention; Kidney; Kidney Diseases; Knowledge; Maintenance; Mediating; Mediator of activation protein; Mesenchyme; Modeling; Molecular; Mus; Nephrology; Nephrons; Organogenesis; Pediatric Hospitals; Play; Process; Publications; Publishing; Regulator Genes; Regulatory Element; Replacement Therapy; Repression; Research; Role; Signal Pathway; Signal Transduction; Testing; Transcriptional Activation; Transcriptional Regulation; Transgenic Organisms; Undifferentiated; Variant; Vesicle; WNT Signaling Pathway; Work; beta catenin; cell type; chromatin immunoprecipitation; combinatorial; cost; genome-wide; improved; invention; mortality; mutant; nephrogenesis; next generation sequencing; notch protein; novel; premature; prevent; progenitor; public health relevance; renal agenesis; response; self-renewal; sound; transcription factor; transcriptome sequencing

DESCRIPTION (provided by applicant): The number of nephrons in a normal kidney shows a wide variation. Low nephron number is correlated with high blood pressure and various renal diseases. In order to generate a sufficient number of nephrons during development, it is critical to balance self-renewal (proliferation) and differentiation (consumption) of nephron progenitors. Self-renewing undifferentiated nephron progenitors express Six2, a transcription factor that is required for the maintenance of the undifferentiated state. Differentiation of these cells involves multiple signaling pathways, two of the most critical being Wnt/beta-catenin and Notch. While Wnt signaling initiates differentiation of the progenitors, Notch signaling is required for further differentiation into proximal tubules. Our recent publication showed that Six2 and Beta-catenin regulate self-renewal and differentiation of nephron progenitors by antagonizing each other through a common set of gene regulatory elements. Still, little is known about the gene regulatory networks regulating the cell fate of nephron progenitors. Our preliminary data suggest that Six2 and Notch2 play important roles during kidney development by regulating expression of common target genes and that Hox proteins participate in the same gene regulatory networks as Notch2. Our goal is to better understand how the cell fate of nephron progenitors is regulated by Six2, Hox, and Notch2, and how nephron progenitors interpret Notch signaling in a context-specific manner through interaction between Notch components and nephron progenitor-specific transcription factors, such as Six2 and HoxD11. To address this, we propose to (1) test the hypothesis that Six2 and Notch2 act as a repressor and an activator, respectively, on common cis-regulatory elements and to (2) test the hypothesis that HoxD11 acts as a mediator of Notch signaling during nephrogenesis. Cell fate decisions of nephron progenitors are determined by complex coordination of multiple transcription factors and signaling pathways. It is critical to identify which target genes are regulated by the transcription factors and to determine how the instructions from various signaling pathways are interpreted by nephron progenitors. Furthermore, understanding how multiple transcriptional regulators downstream of each signaling pathway are orchestrated is essential not only to improve our ability to manipulate nephron progenitors for potential cell replacement therapies but also to develop better ways to prevent or treat renal agenesis or hypoplasia. The results of the proposed research will enhance our knowledge of molecular mechanisms of cell fate decisions and will advance the field of nephrology by providing a better understanding of gene regulatory networks in kidney development. This work is a close collaboration with Steve Potter, an expert in Hox genes, RNA-seq analysis and kidney development, and with Sunghee Oh, an expert in bioinformatics, both my colleagues at Cincinnati Children's Hospital.

描述（由申请人提供）：正常肾脏中肾单位的数量存在很大差异。肾单位数量低与高血压和各种肾脏疾病相关。为了在发育过程中产生足够数量的肾单位，平衡肾单位祖细胞的自我更新（增殖）和分化（消耗）至关重要。自我更新的未分化肾单位祖细胞表达 Six2，这是维持未分化状态所需的转录因子。这些细胞的分化涉及 多种信号通路，其中最关键的两条是 Wnt/β-catenin 和 Notch。虽然 Wnt 信号传导启动祖细胞的分化，但 Notch 信号传导是进一步分化所必需的。 分化为近端小管。我们最近发表的文章表明，Six2 和 Beta-catenin 通过一组共同的基因调控元件相互拮抗来调节肾单位祖细胞的自我更新和分化。然而，人们对调节肾单位祖细胞命运的基因调控网络知之甚少。我们的初步数据表明，Six2 和 Notch2 通过调节共同靶基因的表达在肾脏发育过程中发挥重要作用，并且 Hox 蛋白参与与 Notch2 相同的基因调控网络。我们的目标是更好地了解肾单位祖细胞的细胞命运如何受到 Six2、Hox 和 Notch2 的调节，以及肾单位祖细胞如何通过 Notch 成分与肾单位祖细胞特异性转录因子（例如 Six2 和 HoxD11）之间的相互作用以特定的方式解释 Notch 信号传导。为了解决这个问题，我们建议（1）检验 Six2 和 Notch2 分别作为常见顺式调控元件的阻遏物和激活剂的假设，以及（2）检验 HoxD11 在肾发生过程中充当 Notch 信号传导介质的假设。肾单位祖细胞的细胞命运决定是由多个转录因子和信号通路的复杂协调决定的。确定哪些靶基因受转录因子调节以及确定肾单位祖细胞如何解释来自各种信号传导途径的指令至关重要。此外，了解每个信号通路下游的多个转录调节因子如何协调对于提高我们操纵肾单位祖细胞进行潜在细胞替代疗法的能力至关重要，而且对于开发更好的方法来预防或治疗肾发育不全或发育不全也至关重要。拟议研究的结果将增强我们对细胞命运决定的分子机制的了解，并将通过更好地了解肾脏发育中的基因调控网络来推进肾脏学领域的发展。这项工作是我与 Hox 基因、RNA-seq 分析和肾脏发育方面的专家 Steve Potter 以及生物信息学专家 Sunghee Oh 的密切合作，他们都是我在辛辛那提儿童医院的同事。