Regulation of Erythroid Terminal Differentiation by Long Noncoding RNAs

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员，在那里我可以继续为生物医学研究做出重大贡献。我对RNA的研究有着长期的兴趣，这种兴趣可以追溯到近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。在我在怀特黑德生物医学研究所Harvey Lodish博士实验室的指导研究阶段，我计划利用这个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了解，在功能和机制方面，非编码RNA（lncRNA）多久调节红细胞的发育。在多个步骤中仔细控制红细胞的分化和成熟，以确保红细胞在正常条件下的适当生成。 各种生理条件。重要的是，这一发育过程的功能障碍与许多造血系统疾病有关，如贫血和白血病。虽然许多转录因子和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是未知的。lncRNA是长度超过200 nt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差。越来越多的证据表明lncRNA在发育和细胞功能中起着重要作用。有趣的是，初步研究表明，在红细胞发育过程中，许多lncRNA是动态产生的。重要的是，发现一种名为LincRNA-EPS的红细胞特异性lncRNA通过抑制细胞死亡对红细胞发育至关重要。这些观察结果揭示了这些新RNA对红细胞发育的一个令人兴奋和未被重视的调节层。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（目的1和目的2）。此外，还将建立动物模型，在整个生物体水平上研究LincRNA-EPS的生物学功能（目的1）。最后，将探索其他新鉴定的lncRNA在红细胞发育中的生物学功能（目的3）。本研究的结果将可能导致识别用于治疗各种贫血和骨髓增生异常疾病的新的诊断标记物和/或治疗靶点。

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.