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：
8908006
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/8908006
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 Health 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 analysis in vivo inhibitor/antagonist insight mutant nephrogenesis novel precursor cell premature prevent progenitor repaired research study 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 Sall1 转录因子及其相关染色质重塑复合物如何控制基因调控以产生正常的肾单位禀赋。这将阐明人类遗传综合征和常见散发性出生缺陷的机制，例如肾发育不全（肾脏较小，肾单位数量减少），从而导致肾衰竭。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。 Sall1 的遗传缺陷会改变发育中肾脏的基因表达，加速肾单位分化，导致肾单位祖细胞耗竭和肾脏发育不全。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到上皮的转变来响应典型的 Wnt/ss-catenin 信号，以形成肾单位的大多数管状部分。控制帽间充质这些相反反应的转录机制尚不清楚，但目前的证据表明 Sall1 在这一关键的发育决定中至关重要。我们最近的研究为一种新颖的范式提供了证据。我们提出 Sall1 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 Wnt/ss-catenin 的转录输出来决定肾单位祖细胞的命运。该应用程序将测试该模型结合遗传、基因组和生化方法进行关键预测。 Six2 是肾单位分化的抑制剂。在目标 1 中，我们将确定 Sall1 是否直接上调帽间充质中 Six2 的表达以抑制祖细胞的分化。 Wnt9b（主要分化信号）的表达在 Sall1 突变体中增加。我们将确定增加的 Wnt9b 和减少的 Six2 表达的组合是否足以导致加速肾单位形成和自我更新祖细胞的耗竭。目标 2 将确定 Sall1 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制见解将推动肾单位祖细胞在体外繁殖和/或促进成熟肾小管上皮细胞的再生，以纠正肾单位缺陷。