Health scan: Treatment proposed to prevent devastating inflammation

The HU research group specializes in genetic engineering of mouse models (GEMMs) of inflammation and cancer.

Mouse 311 (photo credit: Courtesy of American Friends of TAU)
Mouse 311
(photo credit: Courtesy of American Friends of TAU)
Experimental work on a mice model that points to a therapy for alleviating a common, severe side effect of chemotherapy and irradiation in cancer patients or patients preparing for bone marrow transplantation has been completed by an international team of researchers from the US and Israel headed by scientists at the Hebrew University of Jerusalem.
Mucositis is a strong inflammatory reaction of the mucosal lining of the digestive system, particularly the gut, and is often a major reason for premature suspension of anti-cancer therapy. As of today, there is no effective way to prevent or treat mucositis.
The HU research group specializes in genetic engineering of mouse models (GEMMs) of inflammation and cancer.
Naama Kanarek, a doctoral student at the Lautenberg Center for Immunology and Cancer Research and the Institute for Medical Research Israel-Canada at the HU Medical Faculty, constructed a mouse model designed to study the effect of deleting a gene encoding the enzyme beta-TrCP. This enzyme was discovered 15 years ago in the laboratory of HU Prof. Yinon Ben-Neriah, in collaboration with the Israeli Nobel Prize laureate Prof. Aaron Ciechanover, as a major regulator of inflammatory cascades.
Kanarek found that beta-TrCP deletion in the gut causes mucosal DNA damage, mimicking the effect of chemotherapy and irradiation. Similarly to human patients, she showed that a severe mucositis reaction occurred in mice that were genetically engineered to be beta-TrCP-deficient.
When they traced the pathological basis of the mouse mucositis, they learned that the source of the problem was interleukin-1 (IL-1 beta), a protein secreted by the stressed mucosa. IL-1 beta was found to abnormally open the gut lining, allowing bacteria to penetrate and destroy the inside of the gut. Even more important was Kanarek’s observation that treating the mice with an antibody that blocks IL-1 beta prevents the onset of mucositis in mice with a beta-TrCP deficiency.
Based on these findings, the researchers proposed that IL-1b beta blocking reagents like anakinra (Kineret), which is used for treating certain chronic inflammatory conditions like rheumatoid arthritis and Crohn’s disease, should be tried for preventing mucositis in humans.
Minimizing a person’s sight for as little as a week may help improve the brain’s ability to process audio input, Baltimore neuroscientists have found. Neuroscience Prof.
Hey-Kyoung Lee, a researcher at the Mind/Brain Institute at the Johns Hopkins University, and colleagues have just published in Neuron a paper on the relationship between vision and hearing.
Music experts often cite blind musicians Stevie Wonder and Ray Charles as examples of how lack of sight can heighten or enhance hearing. Scientists, however, did not fully understand just how that happened until now. With biologist Patrick Kanold at the University of Maryland, Lee’s team was able to uncover how the neural connections in the area of the brain that manages vision and hearing work together to support each sense. These findings could help those experiencing hearing loss regain more use of that sense.
“In my opinion, the coolest aspect of our work is that the loss of one sense – vision – can augment the processing of the remaining sense, in this case, hearing, by altering the brain circuit, which is not easily done in adults,” Lee said.
“By temporarily preventing vision, we may be able to engage the adult brain to now change the circuit to better process sound, which can be helpful for recovering sound perception in patients with cochlear implants for example,” she said.
They placed healthy adult mice in a darkened environment to simulate blindness for about a week and monitored their response to certain sounds. Those responses and brain activity were then compared to those in a second group of mice housed in a naturally lit environment.
The researchers found that mice that experienced simulated blindness had a change in brain circuitry; it occurred in the sound-processing area of the brain – the primary auditory cortex – which allows conscious perception of pitch and loudness.
It seems that not being able to see allows you to hear softer sounds and better discriminate pitch, said Lee. “If you ever had to hear a familiar piece of music with a loud background noise, you would have noticed that sometimes it seems the beat or the melody is different, because some of the notes are lost with the background. Our work would suggest that if you don’t have vision, you can now rescue these ‘lost’ notes to now appreciate the music as is.”
The researchers concluded that a certain set of connectors in the primary sensory areas of the brain, called thalamocortical inputs, are less flexible in humans later in life.
When another sense is impaired, however, those connectors can be reactivated to support the sense that is lagging.
Kanold, whose expertise is in how the brain processes sound, is hopeful that the study’s findings will apply to humans. “We don’t know how many days a human would have to be in the dark to get this effect and whether they would be willing to do that,” Kanold said. “But there might be a way to use multisensory training to correct some sensory processing problems in humans.”
For now, the changes discovered by the group are reversible – the mice that experienced simulated blindness eventually reverted to normal hearing after a few weeks in a normal light-dark environment. In the next phase of their five-year study, the researchers plan to look for ways to make the sensory improvements permanent. They will also look beyond individual neurons to study broader changes in the way the brain processes sounds.