Diamond-Blackfan Anemia and Ribosomal Protein S19

Diamond-Blackfan 贫血和核糖体蛋白 S19

• 批准号: 6951169
• 负责人: Mohandas Narla
• 金额: $ 30.54万
• 依托单位: NEW YORK BLOOD CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6951169
• 关键词: CD34 molecule; NOD mouse; RNA interference; SCID mouse; antiemetics; biological signal transduction; cell differentiation; clinical research; confocal scanning microscopy; congenital aplastic anemia; drug screening /evaluation; erythroid stem cell; erythropoiesis; gene expression; gene mutation; genetic polymorphism; human subject; immunoprecipitation; molecular pathology; phenylamide; prolactin; protein localization; protein protein interaction; protein structure function; protein transport; ribosomal proteins; yeast two hybrid system

DESCRIPTION (provided by applicant): The long-term objective of this new application is to develop a detailed mechanistic understanding of the pathophysiology of Diamond-Blackfan anemia (DBA). Specifically, the role of the ribosomal protein S19 (RPS19) in normal erythropoiesis and in disordered erythropoiesis in DBA will be explored. The rationale for the proposed studies is that although 25% of DBA subjects have been documented to harbor mutations in one allele of the RPS19 gene, there is currently no information on how this protein regulates erythropoiesis. In the present application, we propose to test several hypotheses regarding the pathophysiology of DBA and the role of RPS19 in erythropoiesis: i) altered trafficking and/or expression levels of RPS19 in erythroblasts leads to disordered erythropoiesis; ii) a signal transduction pathway involving a multiprotein complex of RPS19 and its binding partners regulates erythropoiesis; and iii) prolactin is a modulator of in vivo erythropoiesis and that the observed beneficial response to metoclopramide of some DBA affected individuals is through prolactin synthesis and release induced by this treatment. To achieve our stated objectives we have designed a series of studies with the following three specific aims. 1) Study subcellular localization and expression levels of normal and mutant proteins in erythroblasts and determine if conditional haploinsufficiency could account for the pleiotropic character of DBA. Obtain insights into role of RPS19 in erythropoiesis by defining alterations in erythroid differentiation of progenitors following specific inhibition of RPS19 by RNA mediated interference (RNAi). 2) Characterize the binding partners of RPS19 protein and determine if multiprotein complex of RPS19 and its binding partners regulate erythropoiesis. 3) Define the role of prolactin in regulating erythropoiesis and develop mechanistic understanding for the efficacy of metoclopramide in treatment of DBA. We anticipate that successful achievement of the proposed aims will provide fundamental insights into the DBA pathophysiology and the role of RPS19 in erythropoiesis. Furthermore, it is our hope that the new insights generated by our studies might lead to the development of new therapeutic strategies for the treatment of DBA patients presenting with RPS19 gene mutations.

描述（由申请人提供）： 这一新应用的长期目标是对 Diamond-Blackfan 贫血 (DBA) 的病理生理学产生详细的机制理解。具体而言，将探讨核糖体蛋白 S19 (RPS19) 在正常红细胞生成和 DBA 红细胞生成紊乱中的作用。拟议研究的基本原理是，尽管已记录 25% 的 DBA 受试者的 RPS19 基因的一个等位基因存在突变，但目前尚无关于该蛋白质如何调节红细胞生成的信息。在本申请中，我们建议测试关于DBA的病理生理学和RPS19在红细胞生成中的作用的几个假设：i) RPS19在成红细胞中的运输和/或表达水平的改变导致红细胞生成紊乱； ii) 涉及 RPS19 及其结合伴侣的多蛋白复合物的信号转导途径调节红细胞生成； iii) 催乳素是体内红细胞生成的调节剂，并且观察到一些受 DBA 影响的个体对甲氧氯普胺的有益反应是通过该治疗诱导的催乳素合成和释放。为了实现我们既定的目标，我们设计了一系列具有以下三个具体目标的研究。 1) 研究成红细胞中正常和突变蛋白的亚细胞定位和表达水平，并确定条件单倍体不足是否可以解释 DBA 的多效性特征。通过定义 RNA 介导的干扰 (RNAi) 特异性抑制 RPS19 后祖细胞红系分化的变化，深入了解 RPS19 在红细胞生成中的作用。 2) 表征 RPS19 蛋白的结合伴侣，并确定 RPS19 及其结合伴侣的多蛋白复合物是否调节红细胞生成。 3) 明确催乳素在调节红细胞生成中的作用，并加深对甲氧氯普胺治疗 DBA 疗效的机制理解。我们预计，所提出目标的成功实现将为 DBA 病理生理学和 RPS19 在红细胞生成中的作用提供基本见解。此外，我们希望我们的研究产生的新见解可能会导致开发新的治疗策略，用于治疗出现 RPS19 基因突变的 DBA 患者。