Research Overview (publications)
The research in Dr. Xu's laboratory focuses on (1) receptor engineering as a new class of drugs for the treatment of chronic pain, (2) development of new non-opioid analgesics for the treatment of acute and chronic pain, (3) rational design of new therapeutic strategies to treat neuronal injuries during and after global cerebral ischemia, and (4) the molecular and cellular mechanisms underlying the actions of low-affinity neurological drugs such as general anesthetics and alcohols. In the first project, recent activities have been directed towards developing targeted delivery of engineered ion channels to nociceptors to treat chronic pain. In the second project, new drugs that work through the glycinergic receptor pathway are being developed and optimized for potential clinical translation. In the third project, systemic immune modulation and its coupling with the central nervous system (CNS) are investigated to develop new therapies for repercussion injuries. The fourth project involves the 3-D structure and dynamics measurements of ion channel receptors. Dr. Xu is also interested in the biological basis of consciousness (approaching from unconsciousness to consciousness).
Projects
RELIEPH for Interstitial Cystitis
About 7.9 million women and 4.6 million men in the US suffer from interstitial cystitis/bladder pain syndrome (IC/BPS). For many patients, the currently available treatments are inadequate and prone to adverse side effects, including potential dependence and abuse of prescription painkillers. An innovative nonpharmacological approach is being developed in Dr. Xu’s lab to treat the debilitating condition of IC/BPS using a newly developed chemical genetics technology called RELIEPH (Receptor Engineering to Lessen Inflammation-Evoked Pain and Hyperactivity). The technology, which is based on the same principles as optogenetics and DREADD, will install engineered chloride (Cl–) channels into urothelial cells and peripheral nociceptors to control bladder hyperactivity and to alleviate pain in IC/BPS. The central hypothesis is that the expression of non-native Cl– channels in the neuron-like urothelial cells and in peripheral nerves can dynamically re-set the hypersensitization of the peripheral afferents without affecting the process of normal nociception. Two different types of “chemical genetic” designs are being tested in a rat model of IC/BPS. The first type acts passively by sensing inflammatory conditions such as acidosis in urothelial cells and peri-nerve tissues. Since the etiology of IC/BPS is still unknown and inflammation is not always present, the second type is designed to selectively respond to small natural chemicals (including metabolites of certain foods) that would otherwise have little or no analgesic action without the engineered Cl– channels. Promising data have demonstrated the efficacy of these engineered channels in treating inflammatory pain and in restoring three outcome measures (intercontraction intervals, peak micturition pressure, and micturition pressure threshold) in a rat model of IC/BPS. The innovative idea and bold approaches will lead to the development of fundamentally new IC/BPS therapy that will greatly and effectively improve chronic pain management and reduce the risk of prescription drug abuse.
Developing Receptor Therapeutics to Treat Chronic Pain
Pain is a complex sensation with physical and emotional components. Current approaches to treat physical pain focus on screening, optimizing, or developing drug molecules that work on existing targets in the body. The inherent limitations of these conventional approaches are twofold: First, drugs are developed around and are limited to receptors in the CNS with multiple functions. Second, most drugs are active in the brain and thus have psychoactive potential. Dr. Xu’s group is developing a new strategy to provide the peripheral nerves with designed analgesic targets. More specifically, the investigators use non-native ion channels as a form of medication. By creating “drug-able” modulations of peripheral nociceptors, they hope to treat the root of nociceptive and inflammatory pain by titrating the excitability of afferent neurons, thereby elevating the pain threshold proportional to the extent of the pain-evoking pathological conditions. Dr. Xu’s lab is engineering non-immunogenic surveillance Cl– channel receptors, specifically homing for peripheral terminals of the C- and Aδ-fibers and their cell bodies in the dorsal root ganglia. These channels are designed to be silent (non-conducting) under normal physiological conditions and thus will not interfere with normal nociception. The designed channels will either spontaneously respond to inflammation-induced changes in the peripheral tissue environment (such as tissue acidosis due to inflammation) or can be activated by small activating molecules that would otherwise have negligible or no analgesic effects.
Injury Mechanisms and Systemic Immune Responses after Cerebral Global Ischemia
Cardiovascular diseases, which frequently result in cardiac arrest, remain the leading cause of death in the USA. Most patients who are successfully resuscitated after cardiac arrest die in the hospital due to delayed brain injuries. A new therapeutic concept is being developed to manipulate protective immune responses, thereby improving the long-term neurological outcomes by preventing and reversing delayed brain injuries.
This is a collaborative project that brings together two investigative teams at the University of Pittsburgh and Texas Tech University, with many years of combined research experience in (1) the treatment of reperfusion injuries after global cerebral ischemia due to cardiac arrest and resuscitation, (2) mechanisms of neuronal injury and protection through systemic immune responses, and (3) systemic drug delivery to the CNS. The investigators use partially and completely immune-deficient mice to carefully dissect the systemic immune components that can be programmed as post-treatment strategies. They designed a way to condition bone-marrow-derived macrophagic and dendritic cells for immune reconstitution and developed CNS-targeting nanoparticles to knock down pro-inflammatory cytokine signaling using RNA interference technologies. These studies will pave the way towards ultimately identifying the most effective strategies to treat global ischemia after cardiac arrest and to bring the new discoveries from the bench top to the bedside.
Molecular and Cellular Mechanisms Underlying the Actions of Low-Affinity Neurological Drugs
This project focuses on in-depth investigations of the molecular nature of general anesthetic interaction with neuronal membrane constituents. Recent research efforts have combined the use of modern molecular biology techniques with various biophysical approaches, notably state-of-the-art, high-resolution, solution- and solid-state nuclear magnetic resonance (NMR), to elucidate the effects of general anesthetics on the structures and dynamics of the transmembrane segments of the human glycine receptors. The project aims to identify the structure-function and dynamics-function relationships with direct binding and dynamics analyses at the sub-molecular and atomic levels.
Biological Basis of Consciousness
Neurons communicate with each other dynamically, but how such communications lead to consciousness remains unclear. Dr. Xu’s group has developed a theoretical model to understand the dynamic nature of sensory activity and information integration in a hierarchical network. Their mathematical model offers mechanistic insights into the emergence of information integration from a stochastic process and suggests that patients losing consciousness under the influence of anesthesia might be the result of reduced information accessibility in the neural network, which hampers the flow of sensory information. Those findings shed new light on precisely how changes in brain activity can lead to the loss and re-emergence of consciousness.
News & Media Appearances
Lab Members
Principal Investigator: Yan Xu, PhD
Postdoctoral Scholar: Raina Rhoades, PhD
Research Specialist: Thomas Deakin, BS
Staff
Sandy Hirsch, MBA
Lab Contact Info
Yan Xu
Office Phone: (412) 648-9922
Lab Phones: (412) 648-2945
(412) 648-9137
(412) 648-9024
Fax: (412) 648-8998