Regulation of Erythroid Terminal Differentiation by Long Noncoding RNAs

长非编码RNA对红系终末分化的调节

基本信息

批准号：
8485850
负责人：
Wenqian Hu
金额：
$ 11.15万
依托单位：
WHITEHEAD INSTITUTE FOR BIOMEDICAL RES
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8485850
关键词：
Anemia Animal Model Apoptosis Apoptotic Award Back Biochemical Genetics Bioinformatics Biological Biological Assay Biological Process Biomedical Research CFU-E Cell Cycle Cell Death Cell Differentiation process Cell Size Cell division Cell physiology Cells ChIP-seq Chromatin Code Commit Communication Research Data Databases Development Developmental Process Diamond-Blackfan anemia Disease Ensure Erythrocytes Erythroid Erythroid Cells Erythropoiesis Erythropoietin Fetal Liver Gene Expression Gene Expression Profile Generations Genomics Goals Grant Hematopoietic Hemoglobin Hepatocyte Histones Human Institutes Knockout Mice Lead Link Literature Love Mediating Mentors Methods MicroRNAs Modeling Molecular Mus Myelodysplastic/Myeloproliferative Disease Names Organism Orthologous Gene Phase Physical condensation Physiological Play Process Proteins Publishing RNA RNA Polymerase II RNA Splicing RNA-Protein Interaction Regulation Research Research Personnel Resources Role Stimulus Thalassemia Universities Untranslated RNA Variant Whole Organism Withdrawal Writing career cytokine erythroid differentiation gain of function in vivo insight leukemia loss of function mouse model myelodysplastic anemia novel novel diagnostics promoter response skills therapeutic target transcription factor transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): My long term career goal is to become an independent investigator in a leading university where I can continue to make significant contributions to biomedical research. I have a long standing fascination with studies of RNA that dates back almost 10 years, and I would love to commit my career to RNA-related biomedical research. During my mentored research phase in Dr. Harvey Lodish's lab at the Whitehead Institute for Biomedical Research, I plan to use the valuable resource of this award to enhance my skills in scientific research, communication and presentation, grant writing, and lab management. The long term goal of my proposed studies in the Lodish Lab and my own lab is to understand, at both functional and mechanistic fronts, how long noncoding RNAs (lncRNAs) regulate the development of red blood cells. The differentiation and maturation of erythroid cells are carefully controlled at multiple steps to ensure the proper generation of red blood cells under various physiological conditions. Importantly, malfunction of this developmental process is linked to many hematopoietic disorders, such as anemia and leukemia. Although the roles of many transcription factors and microRNAs in red blood cell development are becoming increasingly clear, whether and how lncRNAs regulate this developmental process is largely unknown. LncRNAs are RNAs that are longer than 200nt, and they do not have functional protein coding capacity. These RNAs constitute a significant fraction of the mammalian transcriptome and are poorly conserved in sequence among related organisms. Emerging evidence indicates that lncRNAs play important roles in development and cell functions. Interestingly, the preliminary studies indicate that during red blood cell development, many lncRNAs are dynamically generated. Importantly, an erythroid specific lncRNA named LincRNA-EPS are found to be essential for red blood cell development by inhibiting cell death. These observations reveal an exciting and unappreciated layer of regulation of red blood cell development by these novel RNAs. In this research, the function and molecular mechanisms of how lincRNA-EPS inhibits cell death and facilitates red blood cell differentiation will be investigated (Aim 1 and Aim 2). In addition, animal models will be built to study the biological functions of LincRNA-EPS at the whole organism level (Aim 1). Finally, the biological functions of other newly identified lncRNAs in red blood cell development will be explored (Aim 3). The results of this study will potentially lead to the identification of novel diagnostic markers and/o therapeutic targets for the treatment of various anemias and myelodysplastic disorders.

描述（由申请人提供）：我的长期职业目标是成为一所领先大学的独立研究者，在那里我可以继续为生物医学研究做出重大贡献。我对 RNA 研究一直很着迷，可以追溯到近 10 年前，我很乐意将我的职业生涯致力于 RNA 相关的生物医学研究。在怀特海德生物医学研究所 Harvey Lodish 博士实验室的指导研究阶段，我计划利用该奖项的宝贵资源来提高我在科学研究、沟通和演示、资助写作和实验室管理方面的技能。我在 Lodish 实验室和我自己的实验室提出的研究的长期目标是从功能和机制两个方面了解非编码 RNA (lncRNA) 调节红细胞发育的时间。红细胞的分化和成熟在多个步骤中受到仔细控制，以确保在适当的条件下正确生成红细胞各种生理状况。重要的是，这一发育过程的故障与许多造血系统疾病有关，例如贫血和白血病。尽管许多转录因子和 microRNA 在红细胞发育中的作用越来越清楚，但 lncRNA 是否以及如何调节这一发育过程在很大程度上尚不清楚。 LncRNA是长度超过200nt的RNA，它们不具有功能性蛋白质编码能力。这些 RNA 构成哺乳动物转录组的重要部分，并且在相关生物体中序列保守性较差。新的证据表明 lncRNA 在发育和细胞功能中发挥着重要作用。有趣的是，初步研究表明，在红细胞发育过程中，许多lncRNA是动态生成的。重要的是，一种名为 LincRNA-EPS 的红细胞特异性 lncRNA 通过抑制细胞死亡而被发现对于红细胞发育至关重要。这些观察结果揭示了这些新型 RNA 对红细胞发育的令人兴奋且未被重视的调节层。在本研究中，将研究 lincRNA-EPS 如何抑制细胞死亡和促进红细胞分化的功能和分子机制（目标 1 和目标 2）。此外，还将建立动物模型来研究LincRNA-EPS在整个生物体水平上的生物学功能（目标1）。最后，将探索其他新发现的 lncRNA 在红细胞发育中的生物学功能（目标 3）。这项研究的结果将有可能导致识别新的诊断标记物和/或治疗各种贫血和骨髓增生异常性疾病的治疗靶点。