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顶尖大学的独立研究员，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，这可以追溯到近10年前，我愿意把我的职业生涯献给与RNA相关的生物医学研究。在我在怀特黑德生物医学研究所哈维·洛迪什博士的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、拨款撰写和实验室管理方面的技能。我在罗迪什实验室和我自己的实验室进行的拟议研究的长期目标是，从功能和机制两个方面了解非编码RNA(LncRNAs)调节红细胞发育的长度。红系细胞的分化和成熟受到多步骤的精心控制，以确保红血球在 各种生理状况。重要的是，这一发育过程的障碍与许多造血疾病有关，如贫血和白血病。尽管许多转录因子和microRNAs在红细胞发育中的作用日益明确，但lncRNAs是否以及如何调控这一发育过程在很大程度上尚不清楚。LncRNAs是长度超过200nT的RNA，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组成部分，在相关生物中序列保守性很差。越来越多的证据表明，lncRNAs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lncRNAs是动态产生的。重要的是，一种名为LincRNA-EPS的红系特异性LncRNA被发现通过抑制细胞死亡而对红细胞发育至关重要。这些观察揭示了这些新的RNA对红细胞发育的一层令人兴奋和不为人知的调节。在这项研究中，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，在整个生物体水平上研究LincRNA-EPS的生物学功能(目标1)。最后，将探讨其他新发现的lncRNAs在红细胞发育中的生物学功能(目标3)。这项研究的结果可能会导致识别新的诊断标记和/或治疗靶点，用于治疗各种贫血和骨髓异常增生性疾病。

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.