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) rational design of new therapeutic strategies to treat neuronal injuries during and after cerebral global ischemia, and (3) the molecular and cellular mechanisms underlying the actions of low-affinity neurological drugs. 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, systemic immune modulation and its coupling with the central nervous system are investigated to develop new therapies for repercussion injuries. The third project involves the 3-D structure and dynamics measurements of ion channel receptors. Dr. Xu is also interested in the molecular and cellular basis of consciousness (approaching from unconsciousness to consciousness).
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 central nervous system 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. This innovative idea and bold approach will lead to the development of a fundamentally different class of pain medication that will be particularly efficacious for the management of inflammatory pain and at the same time reduce the problem of prescription drug abuse.
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 proposed to develop a paradigm-shifting strategy to manipulate protective immune responses, thereby improving the long-term neurological outcomes by preventing and reversing delayed brain injuries.
This is a collaborative project which 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 central nervous system (CNS). In their search for effective treatment of global cerebral ischemia using adult stem cells, the investigators discovered a novel mechanism of stem cell protection through cell signaling instead of transdifferentiation or fusion between stem cells and host cells. Most importantly, the investigators found that this signaling process could strongly modulate the inflammation response to global ischemia and render protection to selectively vulnerable neurons by preventing pro-inflammatory damage to glial cells. 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 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.
Molecular and Cellular 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 connectivity in the neural network, which hampers the flow of sensory information. Those findings could help shed light on precisely how changes in brain activity can lead to the loss and re-emergence of consciousness.
News & Media Appearances
Principal Investigator: Yan Xu, PhD
Tommy Tillman, PhD
Lab Contact Info
Office Phone: (412) 648-9922
Lab Phones: (412) 648-2945
Fax: (412) 648-8998