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Stephan Frangakis

MicroRNAs (miRNAs) are a class of small endogenous regulatory RNAs of about 22 nucleotides found in plants and animals. miRNAs bind to complementary messenger RNAs (mRNAs) and target them for cleavage or translational repression. This class of molecules was first discovered in 1993 as a regulator of C. elegans larval development. Recently, more miRNAs (about 300) have been discovered and linked to organism development. In most cases, miRNAs regulate stem and precursor cell division and lineage differentiation.

Cell differentiation is a complex series of molecular events with genes being turned on and off at specific times and expressed in specific amounts. Regulation of genes takes place at several levels; genes may be condensed and packaged in chromatin, pretranscriptionally regulated, postranscriptionally regulated, or regulated during translation. Much of what drives cellular differentiation is not known or understood. However, new research has shown that miRNAs play a significant role in cell differentiation pathways.

Recently, is has been shown that miRNAs are required for proper differentiation in stem/progenitor cells. It has been shown that differentiating embryonic stem cells express a set of miRNAs not found in any other type of cell. Disrupting the enzyme that synthesizes nearly all miRNAs causes embryonic stem cells to be defective in differentiation, as well as inhibiting apoptosis in mature cells. miRNAs have been further implicated in stem cell differentiation using experiments that find miRNAs preferentially expressed in differentiated cells. These miRNAs can then be used ectopically to differentiate progenitor cells.

Project Goals and Significance-

The main goal of this work is to find and isolate fate-specific miRNAs from mature cells. From these learnings the next step will be to induce an undifferentiated stem/progenitor cell to follow several possible cell fates and progress along a specific pathway to form a fully functional differentiated cell. To date this premise has not been reduced to practice. The precise miRNAs used at particular stages of specific cell differentiation pathways are not known. Hence, the determination of fate-specific miRNAs and their differentiation patterns will be an invaluable step towards specifically inducing cell differentiation.

We have so far determined differences in miRNA makeup between embryonic and differentiated cells. By extracting and isolating the miRNAs for several cell types, we have been able to determine which miRNAs are likely responsible for stem cell differentiation. A next step in this project will be to use this knowledge to differentiate stem cells along a desired path.

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