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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：
8638282
负责人：
MICHAEL I RAUCHMAN
金额：
$ 32.95万
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 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8638282
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 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 Genetically Engineered Mouse Genomics Goals Human Human Genetics Hypertension In Vitro Injury Kidney Kidney Diseases Kidney Failure 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 Regulation Renal function Research Risk Signal Transduction Sorting - Cell Movement Stem cells Syndrome Testing Therapeutic Transcriptional Regulation Tubular formation Undifferentiated Ureter Vesicle Work epithelial to mesenchymal transition exhaustion genome wide association study in vivo inhibitor/antagonist insight mutant nephrogenesis novel precursor cell premature prevent progenitor public health relevance repaired research study response self-renewal stemness transcription factor

项目摘要

SUMMARY/ABSTRACT 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.

总结/摘要这项工作的长期目标是确定Sall 1转录因子及其受体是如何被激活的。相关的染色质重塑复合物控制基因调控，以产生正常的肾单位这将阐明机制，人类遗传综合征和常见的零星出生缺陷，如肾发育不全（肾小，肾单位数量减少），导致肾失败形成适当的肾单位的补充需要多能细胞扩张之间的平衡。肾祖细胞和分化。Sall 1基因缺陷改变发育中的基因表达肾，加速肾单位分化，导致肾单位祖细胞和肾发育不全这些未定型的肾单位前体，称为帽间充质，必须响应典型的 Wnt/β-catenin信号通过自我更新或间充质-上皮转化形成大多数细胞，肾单位的管状部分。控制这些相反的反应的转录机制，帽间充质是未知的，但目前的证据表明，Sall 1是关键的发展，决定我们最近的研究为一种新的范式提供了证据。我们建议Sall 1与核小体重塑和脱乙酰酶（NuRD）染色质重塑复合物，以确定肾单位通过调节响应Wnt/β-连环蛋白的转录输出来调节祖细胞命运。该应用程序将使用遗传、基因组和生物化学方法。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表达的组合足以引起加速的肾单位自我更新祖细胞的形成和耗竭。目标2将确定Sall 1和NuRD如何控制肾单位祖细胞中的转录输出，以确定未定型的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械见解将进一步努力在体外增殖肾单位祖细胞和/或促进成熟肾小管的再生上皮细胞，以纠正肾单位缺陷。