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Certain Cell Types Might Hamper miRNA Research

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Efforts to uncover the mechanism through which microRNAs regulate gene expression have thus far resulted in a number of different, and sometimes conflicting, hypotheses.

But according to one researcher, the challenge of pinning down precisely how and to what extent these small RNAs act may be due in part to the type of cellular systems in which the experiments are conducted.

Speaking at this year's American Society of Gene Therapy meeting in Boston, Timothy Nilson, director of the Center for RNA Molecular Biology at Case Western Reserve University, noted that the majority of research looking at miRNA regulation has been done in traditional cultured cells such as HeLa or Drosophila S2, which don't necessarily reflect the real-life situations in which miRNAs function.
Instead, researchers may want to consider expanding their investigations into different cell types, he says, adding that "I think that, perhaps, it may be time for a fresh start.

"In general, it's been accepted that microRNAs down-regulate gene expression … by binding to 3' UTRs of target mRNAs and that this binding leads to a repression of protein synthesis from targeted mRNAs either by degradation or in some way interfering with translation," Nilson says.

It is also generally believed that miRNAs are synthesized in the nucleus as long precursors called pri-miRNAs, processed into pre-miRNAs, then exported to the cytoplasm, where they are cleaved by Dicer into mature miRNAs that are incorporated into so-called miRNA-containing ribonucleoproteincomplexes, or miRNPs.

In the end, though, "if you can think of a mechanism [by which miRNAs function], it's been proposed, and actually there is good data for [them] all," Nilson says. Overall, it is important to keep in mind that "the biogenesis of all microRNAs is thought to be the same, the assembly into RISC … is thought to be the same, [and] microRNAs in general, despite the differences in their sequence, are all physically the same."

Doug Macron

RNAi Notes

Calando Pharmaceuticals announced that it dosed the first patient in its phase I study of CALAA-01, a systemically-delivered RNAi-based cancer drug. The drug targets the M2 subunit of ribonucleotide reductase and is delivered by a nanoparticle delivery system.

Tekmira Pharmaceuticals and Protiva Biotherapeutics completed their merger and will go by the Tekmira name. Meanwhile, Alnylam Pharmaceuticals and Roche will each be making a $5 million equity investment in Tekmira.

Santaris Pharma began testing its hepatitis C drug, SPC3649, in a phase I trial. The drug targets a microRNA expressed in the liver that is used in viral replication.

Datapoint

$4.6 million
Amount Isis Pharmaceuticals will receive from Alnylam Pharmaceuticals based on an IP cross-licensing agreement.

Funded Grants

$97,200/2008
Functions of Piwi proteins and short RNAs in germline
Grantee: Alexei Aravin, Cold Spring Harbor Laboratory
Began: May 1, 2008; Ends: Apr. 30, 2009

Aravin will be analyzing the biogenesis of Piwi interacting RNAs and their role in the germline. He will also look at the small RNAs associated with Piwi proteins, the mechanism behind piRNA biogenesis, and piRNA-Piwi mediated silencing. He says this work can be applied to finding diagnostic markers and therapeutic targets for human infertility.

$223,500/2008
Genetic Analysis of Conserved microRNAs in C. elegans
Grantee: Allison Lynn Abbott, Marquette University
Began: Apr. 1, 2008; Ends: Mar. 31, 2011

Abbott will be identifying the genetic interactions between miRNAs and other miRNAs, signaling components, and transcription factors. She will also identify which C. elegans development regulatory pathways are controlled by miRNAs. She'll look to uncover whether miRNAs modulate or reinforce signaling pathways and if miRNA-mediated post-transcriptional regulation occurs with transcriptional control of downstream targets.

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