Research news tip sheet: story ideas from Johns Hopkins Medicine

SCIENTISTS CREATE MAP OF GATEKEEPER THAT COULD HELP BRAIN CELLS SURVIVE STROKE

Media Contact:
Rachel Butch,
rbutch1@jhmi.edu

Researchers at Johns Hopkins Medicine have revealed the structure of a gatekeeping protein that could one day impact the treatment of conditions such as heart attack and stroke. Understanding the structure of the protein -- known as the proton-activated chloride channel (PAC) -- helps researchers develop ways to reduce permanent damage caused by conditions associated with acidosis, a condition marked by increased acidity in the blood.

A report of the study, was published Nov. 4, 2020 in Nature.

"Knowing the structure of the PAC helps us understand how this acid-sensing protein works in different pH [the measure of acidity or basicity of a solution] and gives us potential ways to manipulate it for better medical outcomes," says Zhaozhu Qiu, Ph.D., assistant professor of physiology at the Johns Hopkins University School of Medicine and co-corresponding author of the study.

The PAC protein is activated when the environment around the cell becomes acidic. Typically, acidity in the body is held at normal levels through constant blood flow. However, when the circulatory system is disrupted by heart disease, stroke or some cancers, the area quickly becomes acidic as cellular waste builds up.

The Johns Hopkins Medicine-led research team first reported the gene sequences encoding this new "acid sensor" in Science last year. In the study, the researchers showed that stroke can over-activate PAC and kill brain cells in mice.

For the current study, Qiu's team worked with collaborators, led by Wei Lü, Ph.D., assistant professor of structural biology at the Van Andel Institute and co-corresponding author of the study, to collect two types of images of the PAC. One was taken in the protein's relaxed state -- at a cell's normal biological acidity level -- and the other in its active state, when the environment is highly acidic.

To create an accurate picture, they used the specialized, high-powered cryo-electron microscope that supercools molecules so they form precise, easily imaged structures at sizes nearly to the atomic level. The images showed that the PAC resembles a wedding bouquet, with parts that move in response to acidic pH. The movement links to the opening of the gate that enables chloride ions to flow in and out of the cell.

"The PAC structures are beautiful! Combined with functional studies, we revealed a completely new acid-sensing mechanism," says James Osei-Owusu, a doctoral student in Qiu's lab and co-first author of the study. "It sets an example for why getting a structure of the protein is really important and provides a blueprint of how the tiny molecular machine works."

The researchers plan to conduct further studies to test the protein-activated channel's sensitivity to acidic environments and screen for drugs that inhibit the chloride movement through it.

"PAC is widely distributed in many tissues," says Qiu. "Its function in healthy cells is still a big mystery. We hope to solve this puzzle in the near future."

STUDY SHOWS JOHNS HOPKINS MEDICINE DEVICE SAFELY TREATS BRAIN SWELLING 'UNDERCOVER'

Media Contact:
Michael E. Newman,
mnewma25@jhmi.edu

It's slightly shorter in length than a credit card and only as thick as a stack of seven pennies, but the medical device known as the valve-agnostic cranial implant (VACI) has proven large in its quality-of-life return for adult patients with hydrocephalus, a dangerous brain swelling. The team that created the VACI, led Johns Hopkins Medicine researchers, recently announced preliminary findings from a multicenter clinical trial that showed -- when compared with traditional shunts used to remove the excess cerebrospinal fluid (CSF) associated with hydrocephalus -- the device successfully treats the condition with fewer complications, enables easier maintenance and monitoring without follow-up surgery, and gives the patient a more normal appearance.

The results are published in the October 2020 issue of The Journal of Craniofacial Surgery.

According to the National Institute of Neurological Disorders and Stroke, hydrocephalus is an abnormal buildup of CSF -- the clear, colorless liquid that protects and cushions the brain -- circulating in the brain's cavities (ventricles). Hydrocephalus occurs when the normal flow and absorption of CSF is blocked, leaving the excess fluid to widen and swell the ventricles. This puts pressure on the brain and keeps it from properly functioning, leading in turn leading to neurological damage and, in severe cases, death.

Hydrocephalus is most commonly treated in adults by implanting a 1-inch-thick shunt device onto the skull and draining the excess CSF through a tube into either the chest cavity or abdomen, where the fluid is absorbed. However, the traditional shunt -- a device that basically has not changed in design since its development over 60 years ago -- has a high risk of complications, such as skin breakdown, infection and long-term scalp pain; typically requires multiple surgeries for repair or replacement throughout a patient's lifetime; and forms a noticeable bump that many patients find aesthetically unpleasing.

"Our team knew there had to be a better solution, so we created the VACI, a pre-molded, computer-designed cranial implant that cradles a shunt invisibly within the 4 to 5 millimeters of skull space between the scalp and the brain," says Chad Gordon, D.O., director of neuroplastic and reconstructive surgery, and professor of plastic and reconstructive surgery at the Johns Hopkins University School of Medicine. "The recent clinical trial was conducted by surgical teams at various institutions to determine if the VACI could improve patient safety and minimize the complications often seen with traditional shunts."

In the trial, 25 adult patients with hydrocephalus -- 14 women and 11 men ranging in age from 22 to 84 -- were fitted with the VACI at four medical institutions. The patients were monitored for an average of 13 months with 23 (92%) reporting no major scalp or shunt-related complications. One patient experienced a scalp wound over a catheter away from the device and another developed a CSF infection. Neither of these complications were related to the VACI.

"Based on its successful performance, we believe that the VACI is a newfound weapon against neurosurgical-induced deformities, postoperative complications and suboptimal surgical outcomes when treating adult hydrocephalus," says Gordon.

The VACI, now known by its trade name InvisiShunt, was first used in a patient in 2018. The device and the surgical procedure for its implantation are part of a new medical discipline being pioneered by Gordon and his Multidisciplinary Adult Cranioplasty Center team to use the cranial bone space -- a field they have dubbed "neuroplastic and reconstructive surgery."

The team's other achievements include the first-ever cranial implants with: (1) closed-loop direct brain neurostimulators for treating epilepsy, and (2) a "smart" wireless biosensor for continuous monitoring of pressure inside the skull after bone removal to relieve traumatic swelling.

"Both eliminate the risks associated with placing bulky devices under the scalp, thereby making the procedures safer and better tolerated by our neurosurgical patients," says Gordon.

Gordon is co-founder of Longeviti Neuro Solutions, which manufactures and markets the InvisiShunt under an arrangement approved by The Johns Hopkins University. Both Gordon and the university are entitled to royalty distributions for the technology. Two other authors, Judy Huang, M.D., and Erol Veznedaroglu, M.D., own stock in the company and serve as a paid consultant, respectively.

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