Tag Archives: science

miRNA takes the center stage of neuropathic pain

A recent publication in Science has touched on the importance of miRNA in regulating major processes in our neuronal system. This paper published by Ernfors group from the Karolinska Institute in Sweden has identified miRNA-183 (miR-183) as an important regulator of neuropathic pain. I found it quite interesting as it highlights the essential, and novel role of miRNA in how we sense pain.

The way how we sense pain can vary depending on our genetic makeup, and during neuropathic pain, mechanical allodynia involves “hypersensitivity of nociceptive neurons and recruitment of touch-activated low-threshold mechanoreceptive LTMR neurons into the nociceptive network”.

Previous research had identified the miRNA-183 cluster is important in regulating pain – over-expression reverse chronic pains, while downregulation causes pain. Emfors group in this paper identified the location of transduction and where miRNA acts on during neuropathy.

In a conditional knockout of miRNA-183 deficient in all neurons, the group found that mice are more susceptible to mechanical pain. This pain is reversible by a marketed drug, called gabapentin (also known as Neurontin), that is commonly used to treat epilepsy, neuropathic pain and hot flashes.

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The group then started to tease out the targets of miR-183 cluster. They identified 18 up-regulated and 15 down-regulated genes, when comparing dorsal root ganglia from conditional KO and control mice in RNAseq. mRNA of Cacna2d1 and -2d2 of pain sensitivity by regulating calcium channel are of interest, as they were both increased in the KO mice. They hypothesized that the dysregulation (deletion) of miR183 cluster leads to increase of 2d1 and 2d2, and that lead to neuropathy (in this case, hypersensitivity to mechanical stimuli)

SNI-induced dystonia was found to correlate with higher response to mechanical stimuli when they delete miR-183 cluster specifically in the LTMR neurons, which can be reversed by Gabapentin. This state was also associated with an increased expression of 2d1 and 2d2. This means that these LTMR neurons could produce pain during neuropathy that can be reversed by gabapentin.

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I guess the big question is how this could be translated into attenuating neuropathic pain in humans. The perception of pain is greatly influenced by our genetic makeup. Identification of specific SNPs in miR-183 cluster that are associated with pain-related disease could be of interest. Using miR-183 to target Cd1 and Cd2 and its targeted genes could be also used as a therapy, however it is unclear how we can specifically target miR-183 on the neurons that matter.

miRNA-based technology and therapeutics still seems to be relatively early. There definitely seems to be great disruptive potential as a potential therapy. But there is certainly concerns regarding understanding its targets and delivery mechanism. Here are the clinical trials ongoing with miRNA:

NIH Trend: Grant funding success rate

The sequestration ordered on March 1, 2013 has led to 5% budget cut in the National Institute of Health (NIH) funding. NIH is a key player in funding scientific research. Based on their website, NIH states that there would be roughly 640 less projects granted in the fiscal year of 2013 compared to 2012.

nih success rate

Diagram 1: The continual decline of application success rate in NIH. The blue bar illustrated the number of applications. The green bar illustrates the number of awarded applications. The pink line illustrates the percentage of success rate.

From the NIH data book, we have extracted the success rate in diagram 1 (above). The success rate has dropped significantly from 30% in 2000 to 17% in 2013. That’s a whooping 13% drop in success rate when the number of applications continues to grow. If you look at the detailed number of awarded application (see below), the number of awards coming from NIH in 2013 is similar to the number of awards between 1998 and 1999. So, is NIH under-funded? Absolutely yes.

nih success rate data

Diagram 2: Decline in the number of awards to a level similar to 1999.

Let’s switch gear and look at the award of R01 success rate. R01 is the “original and historically oldest grant mechanism used by the NIH”. Diagram 3 below shows first-time applicant (blue) and established investigator (in green). It shows that both success rates have dropped significantly since the late 90s. Since mid-2000s, the success rate has plunged below 20%. The success rates for both first timer and established investigators are now at record low.R01 success rate

Diagram 3. Decline of R01 success rate is found in both first time and established investigators

Interestingly, the number of investigators getting the awards is on a steady increase since the late 90s (see diagram 4 below). Despite the number of awards granted in 2013 is similar to the late 90s, the number of investigators continue to increase. This is possibly due to the fact that more applicants are applying for a grant jointly. Furthermore, the decline in the number of awarded grant application has affected first time applicant the most.

R01 number of investigators

Diagram 4. Steady increase of the number awarded investigators since the late 90s. With the recent decline of awards from 2010, the first time applicants have taken the hardest hit.

Whether or not you are a first time applicant or an established investigator, time is tough. There is an steady increase amount of grant applications, while the number of awards plunges to the level from the late 90s. In the next issue, we will continue to look at the trend within graduate students and postdoctoral fellows.

Source: NIH RePORT

MRSA superbug: a global concern

There is an increasing amount of news coverage on the superbug, which is also known as the methicillin-resistant Staphylococcus aureus (MRSA). But how much do you really know? Here, I will talk about the reason why we should be concerned about the spread.MRSA trend

The history of this bacteria, Staph. aureus, can be traced back to the Egyptian mummies, which historians had recovered pathological changes that are consistent with staphalococcal osteomyelitis. Staph. aureus can be found in 20% to 45% of normal healthy adults. In the hospital-associated cases, serious infection is often caused by the bleach of protection. For example, the skin barrier protection is disrupted after going through an invasive surgery, which allows the colonization of Staph. aureus in tissues.

The concern of MRSA grows as the healthcare community now faces with strains of Staph. aureus that are equipped with methicillin and vancomycin resistance genes.

If you look at the timeline (from Nature Magazine), shortly after the introduction of penicillin in the 1940s, some strains of Staph. aureus were already found to have penicillinase/resistance to penicillin. And if you look at when methicillin is introduced to treat Staph. aureus infection, you can see that methicillin resistant strains can be found shortly after the introduction. Typically, vancomycin is used as a last resort due to its toxicity. But the resistance of vancomycin is also emerging.

Are we running out of options to treat Staph. aureus infection? Not now. But if we don’t take action soon to accelerate the antibiotics discovery, we will run out of options when vancomycin resistant strains dominate.