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PROJECT
SUMMARY
MicroRNAs
(miRNAs) are highly conserved small RNA molecules (~21mer)
encoded in the genomes of plants and animals. miRNAs regulate
the expression of genes by binding to the 3'-untranslated
regions (3'-UTR) of specific mRNAs. Each miRNA is thought
to regulate multiple genes in higher eukaryotes making the
potential regulatory functions of miRNAs enormous. While the
role of miRNAs in regulating hematopoiesis has been shown
in lymphoid differentiation, it has not been studied in myeloid
differentiation.
Dendritic cells (DCs) serve a crucial function in the initiation
of potent immune responses, a capacity which makes dendritic
cells an attractive target for therapeutic manipulation in
vaccination and cancer immunotherapy. DCs develop directly
from myeloid progenitors in the bone marrow as well as circulating
blood monocytes. Manipulation of DC differentiation using
miRNAs in monocytes could provide a novel method to utilize
DCs to meet therapeutic needs.
To date, no studies have examined the role of miRNAs in the
in vitro differentiation of dendritic cells from blood monocyte
precursors. Preliminary miRNA microarray expression profiling
revealed distinct differences in miRNA expression in the different
stages of dendritic cell differentiation from blood monocytes.
Preliminary RT-PCR also confirmed the expression of these
unique miRNAs in these differentiated stages. To aid in identifying
true miRNA target genes, computationally predicted target
genes of candidate miRNAs will be ranked using multiple strategies.
Functional analysis programs will be used to predict if relevant
functional groups are inhibited during each stage of differentiation.
Target genes from relevant functional groups will also be
sorted based on the number of candidate microRNAs targeting
that gene. Using this combined strategy, we will more efficiently
identify relevant miRNA target genes for in vitro verification
and reduce the chance of false positives.
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