Regulation of Hematopoiesis by Ribosomal Protein Paralogs

核糖体蛋白旁系同源物对造血的调节

基本信息

批准号：
8816656
负责人：
DAVID L. WIEST
金额：
$ 21.97万
依托单位：
RESEARCH INST OF FOX CHASE CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-01-01 至 2019-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8816656
关键词：
Ablation Acute Lymphocytic Leukemia Acute Myelocytic Leukemia Address Affect Amino Acid Sequence Anemia Animal Model Automobile Driving BMP4 Binding Biogenesis CD34 gene Chimera organism Collection Data Defect Dependence Development Disease Distal Ectopic Expression Equilibrium Gene Silencing Genes Growth Hematopoiesis Hematopoietic stem cells Human Link Messenger RNA Molecular Mus Pathology Pathway interactions Physiological Play Positioning Attribute Process Production Protein Binding Proteins RNA RNA Binding RNA Recognition Motif Regulation Ribosomal Proteins Ribosomes Role Sequence Homology Signal Transduction Specificity Staging Stress Structural Protein Structure Syndrome T-Cell Development T-Lymphocyte Trans-Activators Translational Repression Translations Yeasts Zebrafish base biological adaptation to stress clinically relevant disease-causing mutation fetal human disease insight loss of function mouse model novel paralogous gene progenitor public health relevance skeletal thymocyte

项目摘要

DESCRIPTION (provided by applicant): Ribosomopathies are a collection of diseases caused by mutations in the structural proteins of the ribosome or in proteins that facilitate ribosome biogenesis. It is widely held that the developmental abnormalities that characterize ribosomopathies result from a generalized defect in ribosome biogenesis or function. In contrast to this view, we postulate that ribosomal proteins (RP) have the capacity to bind cellular RNAs outside the context of the ribosome, and that some human diseases are in fact caused by disruption of such distinct, "extra-ribosomal" functions. In support of this hypothesis, we have identified a paralogous pair of RNA-binding RP, Rpl22 and its paralog Rpl22-Like1 (Like1), that are dispensable for both the biogenesis and function of ribosomes, yet perform critical regulatory roles in hematopoiesis. Furthermore, despite their high degree of homology (>70% identical in amino acid sequence), we demonstrate that Rpl22 and Like1 perform distinct functions, i.e., a p53-dependent role in development of �T lymphocytes and a Smad1-dependent role in driving hematopoietic stem cell (HSC) emergence, respectively. Importantly, not only do Rpl22 and Like1 perform distinct functions, but those functions are also mutually antagonistic. Indeed, the block in HSC emergence caused by knockdown of Like1 is rescued by eliminating Rpl22. The fact that the RNA binding helices of Rpl22 and Like1 are identical suggests that these proteins bind largely overlapping sets of RNA targets but have different effects on the activities of those targets. Thus, we now seek to understand how these highly homologous RP perform antagonistic functions that are critical at distinct stages of hematopoiesis. We will do so according to three aims: 1) To determine how systemic loss of Rpl22 causes a selective arrest of developing T cells. 2) To elucidate the basis for the antagonistic functions of Rpl22 and Like1. 3) To understand how the antagonistic balance of Rpl22 and Like1 controls HSC emergence by regulating Smad1.

描述（由申请人提供）：核糖体病是由核糖体结构蛋白或促进核糖体生物发生的蛋白质突变引起的疾病的集合。人们普遍认为，表征核糖体生物发生的发育异常是由核糖体的普遍缺陷引起的。与这种观点相反，我们假设核糖体蛋白 (RP) 具有在核糖体范围之外结合细胞 RNA 的能力，并且某些人类具有这种能力。疾病实际上是由这种独特的“核糖体外”功能的破坏引起的。为了支持这一假设，我们已经鉴定了一对旁系同源的RNA结合RP，Rpl22及其旁系同源物Rpl22-Like1（Like1），它们是可有可无的。此外，尽管它们具有高度的同源性（氨基酸序列> 70%），但我们证明，它们在核糖体的生物发生和功能中发挥着关键的调节作用。 Rpl22 和 Like1 执行不同的功能，即，分别在 T 淋巴细胞的发育中发挥 p53 依赖性作用，在驱动造血干细胞 (HSC) 出现中发挥 Smad1 依赖性作用。重要的是，Rpl22 和 Like1 不仅执行不同的功能，但这些功能实际上也是相互拮抗的，通过消除 Rpl22 的 RNA 结合螺旋可以挽救由敲除 Like1 引起的 HSC 出现的阻碍。 Rpl22 和 Like1 是相同的，表明这些蛋白质结合了大部分重叠的 RNA 靶标，但对这些靶标的活性有不同的影响。因此，我们现在试图了解这些高度同源的 RP 如何执行在造血不同阶段至关重要的拮抗功能。我们将根据三个目标进行此研究：1）确定 Rpl22 的系统性缺失如何导致 T 细胞选择性停滞；2）阐明 Rpl22 和 Rpl22 拮抗功能的基础。 Like1。3)了解Rpl22和Like1的拮抗平衡如何通过调节Smad1来控制HSC的出现。