Receptor Engineering, Non-Opioid Analgesic Development, and Drug Mechanisms

Yan Xu, PhD

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.

RELIEPH for Interstitial Cystitis

NIH/NIDDK R01DK117383-02; Funding Period: 07/01/18-03/31/23; PI: Yan Xu, PhD

About 7.9 million women and 4.6 million men in the US suffer from interstitial cystitis/painful bladder syndrome (IC/PBS). For many patients, the currently available treatments are inadequate and prone to adverse side effects, including potential dependence and abuse of prescription pain medications. An innovative nonpharmacological approach is being developed in Dr. Xu’s lab to treat the debilitating condition of IC/PBS using a chemogenetic 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/PBS. 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/PBS. The first type acts passively by sensing inflammatory conditions such as acidosis in urothelial cells and peri-nerve tissues. Since the etiology of IC/PBS 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/PBS. The innovative idea and bold approaches will lead to the development of fundamentally new IC/PBS therapy that will greatly and effectively improve chronic pain management and reduce the risk of prescription drug abuse.

Discovery and Development of Non-Opioid Analgesic Drugs for Neuropathic Pain Treatment

New Glycinergic Modulators as Potent Painkillers without Negative Psychoactive Effects, NIH/NINDS UG3117383-01S1; Funding Period: 12/15/18-11/30/20; Dual PIs: Yan Xu, PhD and Pei Tang, PhD

Discovery and development of non-opioid analgesics to treat chronic neuropathic pain is an urgent medical need, as current opioid pain medications often lead to drug dependence and abuse. Enhancing activity of glycine receptors (GlyRs) by positive allosteric modulators has emerged as a promising means to treat chronic pain. After a series of structural, electrophysiology, and in vivo studies, Dr. Xu’s lab identified a site in human GlyRs that mediates marijuana’s analgesic action and discovered a new molecular scaffold that binds to the marijuana site, potentiates α3-containing GlyRs with little cross reactivity with opioid receptors and other psychotropic receptors, and suppresses neuropathic and inflammatory pain in rodents with a higher potency than morphine. They have expanded their structure-based drug discovery project and are making significant progress in the development of in vitro and in vivo assays, which benefit the development of not only new glycinergic analgesics, but also new therapeutics in general.

Injury Mechanisms and Systemic Immune Responses after Global Cerebral 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 long-term neurological outcomes by preventing and reversing delayed brain injuries. This is a collaborative project that brings together 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 bring 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.