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Regulation of Nephron Progenitor Cell Self-Renewal and Differentiation

肾单位祖细胞自我更新和分化的调节

基本信息

批准号：
9258431
负责人：
MICHAEL I RAUCHMAN
金额：
$ 12.83万
依托单位：
SAINT LOUIS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-07 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9258431
关键词：
Agonist Binding Binding Sites Biochemical Cell Differentiation process Cells ChIP-seq Childhood Chromatin Remodeling Factor Chronic Kidney Failure Complement Complex Congenital Abnormality Deacetylase Development Differentiated Gene Differentiation Inhibitor Elements Embryo End stage renal failure Endowment Enhancers Ensure Epigenetic Process Epithelial Epithelial Cells Equilibrium Gene Expression Gene Expression Regulation Gene Targeting Genes Genetic Genetic Transcription Genetically Engineered Mouse Genomics Goals Human Human Genetics Hypertension In Vitro Injury Kidney Kidney Diseases Kidney Failure Knock-in Knock-in Mouse Knowledge Life Maintenance Maps Mesenchyme Messenger RNA Modeling Molecular Mus Mutant Strains Mice Mutate Natural regeneration Nephrons Nucleosomes Organ Organ Culture Techniques Output Patients Play Population Recruitment Activity Regulation Renal function Research Risk Signal Induction Signal Transduction Stem cells Syndrome Testing Therapeutic Transcriptional Regulation Tubular formation Undifferentiated Ureter Vesicle Work beta catenin epithelial to mesenchymal transition exhaustion experimental study genome-wide analysis in vivo inhibitor/antagonist insight mutant nephrogenesis novel overexpression precursor cell premature prevent progenitor public health relevance repaired response self-renewal stemness transcription factor

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of the proposed work is to determine how the Sall1 transcription factor and its associated chromatin remodeling complexes control gene regulation to generate a normal endowment of nephrons. This will illuminate mechanisms that underlie human genetic syndromes and common sporadic birth defects, such as renal hypoplasia (small kidneys with reduced numbers of nephrons), which result in kidney failure. Formation of the proper complement of nephrons requires a balance between expansion of multi-potent renal progenitor cells and differentiation. Genetic deficiency of Sall1 alters gene expression in the developing kidney, accelerating nephron differentiation leading to a depletion of nephron progenitor cells and renal hypoplasia. These uncommitted nephron precursors, termed cap mesenchyme, must respond to canonical Wnt/ß-catenin signals by either undergoing self-renewal or mesenchymal-to-epithelial transition to form most tubular segments of the nephron. The transcriptional mechanisms that control these opposing responses of the cap mesenchyme are not known, but current evidence argues that Sall1 is pivotal in this critical developmental decision. Our recent studies provide evidence for a novel paradigm. We propose that Sall1 cooperates with the Nucleosome Remodeling and Deacetylase (NuRD) chromatin remodeling complex, to determine nephron progenitor cell fate by regulating the transcriptional output in response to Wnt/ß-catenin. This application will test key predictions of this model using a combination of genetic, genomic, and biochemical approaches. Six2 is an inhibitor of nephron differentiation. In Aim 1, we will determine if Sall1 directly up-regulates Six2 expression in cap mesenchyme to restrain differentiation of progenitor cells. Expression of Wnt9b, the main differentiation signal, is increased in Sall1 mutants. We will determine if the combination of increased Wnt9b and reduced Six2 expression are sufficient to cause accelerated nephron formation, and exhaustion of self-renewing progenitor cells. Aim 2 will determine how Sall1 and NuRD control the transcriptional output in nephron progenitor cells to determine whether the uncommitted precursor cells undergo self-renewal or initiate nephron differentiation. The mechanistic insights gained from these studies will advance efforts to propagate nephron progenitors in vitro and/or promote regeneration of mature tubular epithelial cells in order to correct nephron deficits.

描述（由申请人提供）：拟议工作的长期目标是确定Sall 1转录因子及其相关的染色质重塑复合物如何控制基因调节以产生正常的肾元天赋。这将阐明人类遗传综合征和常见的散发性出生缺陷的机制，如肾发育不全（肾单位数量减少的小肾脏），导致肾衰竭。肾单位的适当补充的形成需要多能肾祖细胞的扩增和分化之间的平衡。Sall 1基因缺陷改变了发育中肾脏的基因表达，加速了肾单位分化，导致肾单位祖细胞耗竭和肾发育不全。这些未定型的肾单位前体，称为帽间充质，必须通过自我更新或间充质向上皮转化来响应经典的Wnt/β-连环蛋白信号，以形成肾单位的大多数管状节段。控制帽间充质的这些相反的反应的转录机制是未知的，但目前的证据表明，Sall 1是关键在这个关键的发展决定。我们最近的研究为一种新的范式提供了证据。我们提出Sall 1与核小体重塑和脱乙酰酶（NuRD）染色质重塑复合物合作，通过调节响应Wnt/β-连环蛋白的转录输出来决定肾单位祖细胞的命运。该应用程序将测试使用遗传学、基因组学和生物化学方法的组合对该模型进行关键预测。Six 2是肾单位分化的抑制剂。在目标1中，我们将确定Sall 1是否直接上调帽间充质中Six 2的表达以抑制祖细胞的分化。在Sall 1突变体中，主要分化信号Wnt 9 b的表达增加。我们将确定增加的Wnt 9 b和减少的Six 2表达的组合是否足以引起加速的肾单位形成和自我更新祖细胞的耗竭。目标2将确定Sall 1和NuRD如何控制肾单位祖细胞的转录输出，以确定未定型前体细胞是否进行自我更新或启动肾单位分化。从这些研究中获得的机制见解将促进体外繁殖肾单位祖细胞和/或促进成熟肾小管上皮细胞再生以纠正肾单位缺陷的努力。