MicroRNAs (miRNAs) are an abundant and highly conserved class of endogenous ~22-base RNAs that play crucial roles in cell function and development by base pairing to sites within target mRNAs, triggering either translational repression or mRNA degradation, or both. Our long-term goal is to discover the regulatory roles of several conserved miRNAs in critical and well-defined stages in formation of erythrocytes - uncovering not only their specific mRNA targets at both the BFU-E and CFU-E developmental stages but also the underlying network of miRNAs and their mRNA targets essential for these developmental transitions.
Our specific aims are 1) to investigate the functions of miR-144, 451, 221, 222, and 223 in terminal proliferation and differentiation of CFU-E progenitors. We will determine the cellular effects on erythroid differentiation of ectopically overexpressing or knocking down expression these miRNAs in cultured CFU-E cells. Next we will determine the developmentally important mRNA targets downregulated by each of these miRNAs during specific stages of CFU-E proliferation and differentiation using a combination of experimental and computational approaches, and we will determine the roles of selected key miRNA target interactions during erythroid differentiation in culture.
In Aim 2 we will use similar techniques to determine the functions of miR- 221, miR-222, miR-223 and other developmentally regulated miRNAs in the proliferation of BFU-E progenitors and the formation of CFU-Es. These studies will provide important information on the gene regulatory circuitry that controls hematopoiesis, and provide insights into pathological states caused by aberrant expression of certain miRNAs.
The formation of red blood cells in the proper amounts and at proper times is important for health;many anemias and other blood diseases are caused by defects in these processes. MicroRNAs are a recently identified class of small RNAs that help regulate how much protein is produced from individual genes, and in this way they play crucial roles in regulating cell function and development. Our goal is to uncover the functions of several microRNAs that are induced or repressed at defined times during formation of red blood cells and thereby learn how microRNAs are participating in the formation of these cells, and how their dysfunction could contribute to human disease.
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