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Current Research

A. High-Resolution Channel Protein Structure and Function

About 25-33% of all open reading frames in almost every genome encode proteins with one or more membrane spanning domains.  Unfortunately, most of the membrane proteins or membrane-associated proteins are refractory to high-resolution structural determination.  For ligand-gated receptor channels in particular, many important functional features have been unveiled in recent years by mutagenesis and single-channel recording techniques.  The structural basis of their function, however, remains elusive.

Dr. Xu's group is one of the leading groups in the world to combine the high-resolution and solid-state NMR techniques to solve membrane protein structures at the atomic resolution.  The current focus is on the transmembrane domain structures of the human glycine receptor (GlyR), the primary inhibitory receptor in the spinal cord and the brain stem.  Dr. Xu employs the modern molecular biology techniques to label proteins, segment by segment, with non-radioactive and "NMR-visible" isotopes.  This technique allows for the strategically selected transmembrane domains to be studied in the context of a fuller protein that is made "NMR-silent" by the state-of-the-art NMR editing techniques.  Using this and other related approaches, Dr. XU's group has solved the first high-resolution structure of the second and third transmembrane domains of GlyR.

GlyR belongs to a superfamily of receptors called "Cys-loop" receptors.  Mulfunction of these receptors are responsible for many devastating neurological diseases, including the startle disease (hyperekplexia), epilepsy, and Parkinson's disease.  A structural understanding of the function of these receptors will lead to new treatment strategies and better designs of disease-specific drugs with minimal side effects.

B. Molecular Mechanisms of General Anesthesia

General anesthesia is arguably one of the greatest achievements of the mankind, yet the molecular mechanisms of action of general anesthetics remain unknown. In the painstaking search for a molecular understanding of this medical wonder, the thinking has been directed to one of the two putative target sites: the lipid portion of neuronal membranes or the hydrophobic pockets in certain crucial excitable proteins.  The lipid theory believes that general anesthetics cause a generalized perturbation to the neuronal membranes through nonspecific interactions, whereas the protein theory contends that anesthetics must bind specifically to a set of appropriate molecular dimensions on the membrane proteins to produce the effect.  Nevertheless, intensive studies along these lines have not revealed an unequivocal mechanism of general anesthesia.

Dr. Xu's group has been using various biophysical approaches and modern molecular biology techniques to elucidate the effects of general anesthetics on the structures and dynamics of membrane proteins. Unlike many functional analyses that establish the protein sequence-function relationship based on inferences from anesthetic sensitivity, Dr. Xu's approach aims at identifying the structure-function and dynamics-function relationships with direct binding and dynamics analysis at the sub-molecular and atomic levels.  Research in Dr. Xu's lab helped to establish the concept that amphiphilicity, not hydrophobicity, is the crucial element for anesthetic action.  Dr. Xu and colleagues are the first to propose a new protein theory of general anesthesia based on global protein dynamics.  This theory reconcile the many apparent differences exhibited by a diverse range of anesthetics on a diverse range of putative protein targets, thereby suggesting a common (or unitary) molecular event responsible for the physiological effects of general anesthesia.

C. MRI of Brain Protection after Cardiac Arrest and Resuscitation

More than 5 million years of potentially life are lost each year in the United States alone due to cardiovascular diseases.  Each year more than 500,000 people, who are otherwise physically competent to live on average 10 years longer, die of cardiac arrest.  Among the 70,000 patients who are successfully rescued by cardiopulmonary resuscitation (CPR), 60% subsequently die in hospital as a result of extensive brain damage, and only 3-10% can resume their former life activities.

Such a poor long-term outcome is due to the lack of knowledge of the molecular and cellular events responsible for the secondary derangement of the so-called post-resuscitation syndrome.  The research into the pathophysiological mechanisms of neuronal death caused by cerebral hypoxia (a lack of oxygen) and ischemia (an insufficient blood supply) has been largely focused on models of focal or incomplete forebrain ischemia.  Very few studies deal with cerebral protection and resuscitation after global ischemia, such as in the case after a cardiac arrest.  An effective therapeutic strategy to treat reperfusion injury is yet to be devised.

Dr. Xu’s laboratory has developed a clinically relevant cardiac arrest and resuscitation model that is fully compatible with the noninvasive magnetic resonance spectroscopy and imaging techniques, thus permitting pharmacological intervention and long-term outcome to be investigated.

The current research efforts are directed at combining new innovations in the powerful gene therapy and stem-cell therapy with the state-of-the-art MRI techniques.  The focus is on the interventions to restore the health of the microvasculature, thereby correcting the abnormal vascular responses to ischemia and reperfusion.  We are also exploiting the causal interaction between angiogenesis (blood vessel regeneration) and neurogenesis (neuronal repair and regeneration).  This research will lead to the most effective, multifaceted, therapeutic mechanisms and regimens to improve the outcome of cardiac arrest and stroke patients.