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University of Washington’s Thomas Moeller On The Role of Glial microRNAs in Disease

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NAME: Thomas Moeller
 
POSITION: Research associate professor, neurology, University of Washington
 
BACKGROUND:
Research assistant professor, neurology, University of Washington — 2000-2005
Acting assistant professor, neurology, University of Washington — 1998-2000
Senior research fellow, neurology, University of Washington — 1998
PhD, neuroscience, Max Delbruck Center for Molecular Medicine/Free University, Berlin — 1996
MSc, biology, Ruprechts Karl University — 1992
 
At the University of Washington, Thomas Moeller investigates neuroinflammation and its role in neurodegenerative disease. As part of his work, he recently won a two-year grant, worth $170,625 in its first year, from the National Institute of Neurological Disorders and Stroke to examine the role of microRNAs in microglia activation.
 
This week, RNAi News spoke with Moeller about the effort.
 

 
Let’s start with an overview of your lab.
 
My lab studies neuroinflammation … which plays a role in acute diseases like stroke but also neurodegenerative diseases like amyotrophic lateral sclerosis and Huntington’s disease. That’s the more disease-relevant aspect [of my work]. The basic science part of my lab is working on microRNAs.
We started about a year and a half ago looking into how microRNAs are regulated during the activation of immune cells in the brain.
 
Was it the growing body of literature suggesting that microRNAs are involved in all sorts of [biological events] that got you looking at them?
 
We’ve been doing RNAi [for research purposes] for quite awhile, [but] in macrophages RNAi is extremely difficult [to achieve]. … When I read about microRNAs, [I] thought, “Oh my God, not another thing I have to try to get working in brain macrophages.”
 
Then I [investigated] a little more and became fascinated. … When we first started, there was a little bit of literature about the responses of microRNAs in peripheral immune cells. But in the CNS, people mainly looked at neurons, and only 10 percent of brain cells are neurons; 90 percent are so-called glia. Glia is the Greek word for glue, so when people looked at [the brain] 130 years ago, they thought it was all glue between the neurons; it turns out that it is not.
 
There are three main types of glia: astrocytes, oligodendrocytes, and microglia, [which] are the resident brain macrophages. My lab has been working on these immune cells for the last 10 years, trying to understand what makes these cells tick. How do they sense injury or disease in the brain, and what are their response patterns?
 
In macrophages, there was always quite a bit of mystery [over] how certain things are regulated. Typical examples are TNF-alpha, IL-6, IL-1 beta — they all have AU-rich elements in the 3’ UTR, and it just clicked for me that microRNAs might actually play a role in this. So we started to look at the regulation of microRNAs in brain macrophages.
 
Where are you starting from in the grant project?
 
We more or less started out [by asking], “Are there any microRNAs regulated during the [immune] activation process?”
 
The way macrophages get activated is [through] inflammatory and anti-inflammatory [responses]. The inflammatory response is usually in the periphery. [For example, when] you cut yourself and get inflammation, swelling, and pain — there is a similar, but adapted, response in the brain [to injury].
We used a very strong … activator of macrophages to see if would cause any microRNAs to change.
 
And you identified microRNA-155.
 
We identified several microRNAs … that are either up- or down-regulated during the microglia activation process. MiR-155 is one of them.
 
What made this microRNA stand out from the others?
 
It was strongly regulated. What we learned is that it has very low expression at baseline, but it is very strongly up-regulated [during microglia activation]. On the other hand, we have microRNAs that are strongly expressed during normal microglia behavior and are strongly down-regulated during activation.
 
So what we’ve done — and this is becoming more and more [prominent] in the literature — is use microRNA arrays [in parallel] with regular mRNA arrays to do some target prediction.
 
When microRNAs go up, their targets should go down, and when microRNA [expression] goes down, targets should go up. Of course, this only works with microRNAs that are regulated [based] on their abundance and not on the translational level. So we limit ourselves to what we can easily detect, and in this way we identified a number of potential targets for the different microRNAs.
 
And we recently have overcome the problem of macrophage transfection using an Amaxa system. What we do now is take microRNA agonists or antagonists and transfect them into the cells, then look at predicted targets to see if they are up- or down-regulated.
 
In this way, we found new targets [that have previously been identified as] targets of miR-155. And we’ve seen [this to be the case] in the brain.
 
What roles does miR-155 have?
 
It’s still very early. We know it is regulating some specific immune-related genes. What that actually means, we don’t know at the moment. [A collaborator], Antony Rodriguez, who was at Sirna [Therapeutics] and is now at [Baylor College of Medicine], made miR-155 knockout mice, and we are going to isolate macrophages from these mice to see what is actually different [compared with normal mice].
 
We’re going to look for typical microglia activation parameters like proliferation and cytokine release, with a special emphasis on the targets we have identified for miR-155 — how they are regulated or not regulated when miR-155 is not there.
 
What about the implications for this work?
 
At the moment, it is very basic research because we don’t understand what [miR-155] really does. MicroRNAs in the [central nervous system] are quite interesting; there are more reviews out there than primary papers. Everybody who can spell microRNA writes a review about them, but there is just a handful of papers that show regulation of microRNAs in the brain.
 
I just got funded [by the ALS Association with a three-year, $230,000 grant] to look at microRNA regulation in [tissue samples from patients with] ALS. When we look at the spinal cord of mice that carry the same [SOD-1] mutation as [familial] ALS patients, we found that some microRNAs are strongly dysregulated. For example, miR-132, which is important in neuronal housekeeping, viability, [and] memory formation, drops very strongly in these mice.
 
We’re going to look at what’s happening in [the tissue samples and replace down-regulated miRNAs] … and hope to thereby change the disease. [We’d chose miRNAs] that have known [roles] in neuronal processes, like miR-132, or ones that are the most strongly dysregulated.
 
I also just put in another grant [application to the National Institutes of Health to build on work where we] looked at the expression levels of microRNAs in isolated astrocytes and [examined] how they changed when astrocytes get activated by molecules for which they have receptors. What we found is that during the activation process, microRNAs are regulated [including ones that have been found to be expressed in both astrocytes and neurons].

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