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.
This study will not only reveal how long noncoding RNAs regulate erythropoiesis, but also provide insights into how this new layer of regulation is integrated into existing regulatory networks of red blood cell development. Importantly, dys-regulation of erythropoiesis is the cause of many hematopoietic diseases. Thus, the results of this study may also lead to identification of novel diagnostic markers and/or therapeutic targets for the treatment of various anemias and myelodysplastic disorders.
|Alvarez-Dominguez, Juan R; Hu, Wenqian; Gromatzky, Austin A et al. (2014) Long noncoding RNAs during normal and malignant hematopoiesis. Int J Hematol 99:531-41|
|Alvarez-Dominguez, Juan R; Hu, Wenqian; Yuan, Bingbing et al. (2014) Global discovery of erythroid long noncoding RNAs reveals novel regulators of red cell maturation. Blood 123:570-81|
|Hu, Wenqian; Yuan, Bingbing; Lodish, Harvey F (2014) Cpeb4-mediated translational regulatory circuitry controls terminal erythroid differentiation. Dev Cell 30:660-72|