The Johns Hopkins University
Dr. Dong is also a professor of neuroscience, neurosurgery, and dermatology at the Johns Hopkins University School of Medicine. He was an HHMI early career scientist from 2009 to 2015.
Molecular and Genetic Studies of Pain-sensing Neurons
Xinzhong Dong knew the family of proteins he discovered as a postdoctoral researcher was diverse. But he couldn't have known that, by continuing to study those proteins in the ensuing years, he would revolutionize the field of itch research by revealing how the brain discriminates itch from pain, and by uncovering why certain drugs cause allergy-like side effects despite not triggering a true allergic reaction.
The proteins Dong studies are cellular receptors called Mrgprs. Several members of the Mrgpr family are found only in sensory neurons, and Dong showed that they function as itch receptors. His team has shown that itch-sensitive nerve cells are distinct from pain-sensing neurons.
Dong's team recently discovered that another Mrgpr is produced exclusively on mast cells – immune system first responders that recruit other immune cells to the site of an injury. This receptor is sensitive to a variety of compounds that trigger the mast cells' call to arms, the researchers found, including components of animal venoms, therapeutic drugs, and inflammation-triggering peptides. Pseudo-allergic drug responses, which are common for a variety of drugs and can range from local inflammation to life-threatening anaphylaxis, are eliminated in mice whose mast cells lack Mrgpr receptors.
Pain, itch, gentle touch. These three vastly different sensations all start from the same place—a bundle of nerves at the base of the spine known as the dorsal root ganglion. At the Johns Hopkins University School of Medicine, neuroscientist Xinzhong Dong is uncovering the molecular and cellular basis of all three, with an eye toward better treatments for chronic pain and itch.
Dong's interest in biology began early on, with almost daily trips with his father to the zoo in Beijing. He spent summer days digging up cicada nymphs that had burrowed underground and watching their metamorphosis from pupa to adult. Today he studies the inner workings of sensory neurons.
Dong first began studying sensory biology as a postdoctoral fellow at the California Institute of Technology. In the lab of HHMI investigator David Anderson, Dong searched for genes that were expressed only in sensory nerves, expecting they would likely have important roles in those cells. He identified genes responsible for a family of about 50 protein receptors, known as Mrg receptors, that are expressed in mice only in dorsal root ganglion neurons. "We were really excited about the discovery of these genes," he says. "But for a long time we didn't really know what these genes do, except that they are highly specifically expressed in dorsal root ganglia."
In his Hopkins lab, Dong is uncovering the function of these genes by combining genetic and behavioral studies in mice with electrophysiology, biochemistry, and molecular biology to reveal how signals triggered by the Mrg receptors are processed as they travel from the skin to the spinal cord.
His recent studies have shown that these receptors play a role in certain kinds of itch sensations. In some people, the antimalarial drug chloroquine causes an extremely unpleasant itching that is not relieved by antihistamine medications. The itching can be so intense that many people stop taking the drug. Normal mice that receive chloroquine react similarly to humans, but mutant mice lacking certain Mrg receptors show a drastic reduction in scratching behavior. These mice seem to be immune to chloroquine's itch-inducing side effects.
On the basis of these studies, Dong determined that a small subset of dorsal root ganglion neurons is dedicated to itch sensation. Now he can perform experiments to visualize where the neurons begin and end and which neurons they send signals to in the spinal cord. He intends to examine the effects of genetically removing them in mice.
Dong is also pursuing the relationship between itch and pain sensations. Some pain relievers, such as morphine, can have itchy side effects. And the pain caused by scratching can make an itch subside, at least temporarily. This antagonistic relationship is not well understood, but Dong hopes that a better understanding of the sensory pathways will illuminate where this effect occurs.
He is working on several projects to identify and describe the pain pathways and hopes to find new drugs for treating chronic pain. "We really need a novel and specific drug target," he says. He has observed that activating one of the Mrg receptors can inhibit chronic pain in mice and causes no visible problems. "The specificity of these genes makes them great candidates for drug development because it minimizes side effects," unlike most commonly used medications for chronic pain, Dong says.
Gentle touch, his third area of research, is perhaps the least understood. Preliminary studies suggest that one Mrg gene, which is expressed in a small subset of dorsal root ganglion neurons, might be involved in perceiving gentle touch. If his experiments confirm that these neurons detect gentle touch, he wants to explore how that sensation provokes feelings of comfort and pleasure in the brain.