Research Roundup: Getting the Inner Ear to Regenerate and More

Inner Ear

Every week there are numerous scientific studies published. Here’s a look at some of the more interesting ones.

Getting the Inner Ear to Regenerate

Investigators at Keck School of Medicine of USC identified a natural barrier to the inner’s sensory cells’ ability to regenerate. This ability is lost in hearing and balance disorders. There are two major types of sensory cells in the inner each, which is the cochlea: “hair cells” that receive sound vibrations and “supporting cells” that have structural and functional roles. When damage occurs to the hair cells, such as from loud noises or some prescription drugs, in older mammals the hearing loss is permanent. But in young laboratory mice, in the first few days of life, they can still repair the hair cells via “transdifferentiation,” which allows for the recovery of hearing. Mice lose this after about a week, and so do humans, probably before birth.

“Permanent hearing loss affects more than 60% of the population that reaches retirement age,” said Neil Segil, professor in the Department of Stem Cell Biology and Regenerative Medicine, and the USC Tina and Rick Caruso Department of Otolaryngology – Head and Neck Surgery. “Our study suggests new gene engineering approaches that could be used to channel some of the same regenerative capability present in embryonic inner ear cells.”

In the supporting cells of the cochlea in newborn mice, they found that the hair cell genes were suppressed by loss of H3K27ac, an activating molecule, and the presence of H3K27me3, a repressive molecule. But the hair cell genes of the mouse supporting cells were primed to activate when in the presence of H3K4me1. But with age, the supporting cells lose HeK4me1, leaving that primed state. But if they added a drug to prevent the loss of H3K4me1, the supporting cells stayed primed for transdifferentiation. The researchers believe this opens the possibility of using drugs or gene editing to make epigenetic modifications that could restore hearing.

Early COVID-19 Symptoms Vary Among Age Groups and Between Men and Women

A study out of King's College London found significant differences between age group symptoms in people 16 years to 59 years and 60 to 80 years and over for COVID-19. They also found different early symptoms between men and women. The study evaluated 18 symptoms and found the most important symptoms for early detection of COVID-19 overall were loss of smell, chest pain, persistent cough, abdominal pain, blisters on the feet, eye soreness and unusual muscle pain. But in people over 60, loss of smell lost significance and was not relevant in people over 80. Other early symptoms such as diarrhea were key in the 60 and older groups, while fever was not an early feature in any age group, although it is a known symptom. Men were more likely to report shortness of breath, fatigue, chills and shivers. Women were more likely to report loss of smell, chest pain and persistent cough.

Cardiosphere-Derived Exosomes to Treat Acute Trauma

Capricor Therapeutics and the U.S. Army Institute of Surgical Research published research on cardiosphere-derived exosomes (CDC-EVs) that showed they can attenuate kidney damage and promote new blood vessel formation in a preclinical model of acute trauma. The research is a way of developing ways to stabilize wounded warriors in the field. An exosome is a type of extracellular vesicle that contains proteins, DNA and RNA of the cells that secrete them. They can be taken up by cells that are at a distance, and affect their cell function and behavior. Cardiosphere-derived cells are a cardiac progenitor cell population that has been shown to have cardiac regenerative properties and may be able to improve heart function in some cardiac diseases. The goal of this study was to show that CDC-EVs could help in a rat model of acute traumatic coagulopathy induced by polytrauma and hemorrhagic shock. The data suggests early deliver could improve outcomes.

Too Much Sugar Negatively Affects Mitochondrial Function

Investigators with the Van Andel Research Institute found that surplus sugar can cause mitochondrial, the energy manufacturers of our cells, to become less efficient and decrease energy output. They found that too much cellular glucose, which is directly associated with the amount of sugar in the diet, affected lipid (fat) composition throughout the body, which affects the integrity of mitochondria. Too much sugar decreased the concentration of polyunsaturated fatty acids (PUFAs) in the mitochondrial membrane, making mitochondria less efficient. They were able to reverse the effect in mice by feeding them a low-sugar ketogenic diet.

New Target for Aggressive Cancers

Researchers with the Wellcome Trust Sanger Institute, University of Cambridge and Harvard University identified a protein that plays a major role in transforming normal tissue into cancer. They believe this will be a potential new target for certain aggressive cancers. Using CRISPR-Cas9 gene editing to screen cancer cells, they identified the METTL1 gene, which produces the RNA-modifying METTL1 protein. Mutations in the METTL1 gene lead to higher levels of the METTL1 protein, which causes cells to replicate faster and become cancerous, which creates highly aggressive tumors. When inhibiting the METTL1 protein by knocking out the gene, it halted cancer cell growth while leaving the normal healthy cells unharmed.

The Achilles’ Heel of Ovarian Cancer

Scientists at UT Southwestern Medical Center discovered that ovarian cancers massively amplify NMNAT-2, an enzyme that makes NAD+. NAD+ is a substrate for a family of enzymes known as PARPS, which modify proteins with ADP-ribose from NAD+. One of the PARPs, PAR-16, uses NAD+ to modify ribosomes, which are the machinery in the cell that synthesizes proteins.

“We were able to show that when ribosomes are mono(ADP-ribosyl)ated in ovarian cancer cells, the modification changes the way they translate mRNAs into proteins,” said W. Lee Kraus, professor of Obstetrics and Gynecology and Pharmacology and a member of the Harold C. Simmons Comprehensive Cancer Center. “The ovarian cancers amplify NMNAT-2 to increase the levels of NAD+ available for PARP-16 to mono(ADP-ribosyl)ate ribosomes, giving them a selective advantage by allowing them to fine-tune the levels of translation and prevent toxic protein aggregation. But that selective advantage also becomes their Achilles’ heel. They’re addicted to NMNAT-2, so inhibition or reduction of NMNAT-2 inhibits the growth of the cancer cells.”

At this time, there are no PARP-16 inhibitors in clinical trials, but there are labs working to develop PARP-16 inhibitors.

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