Both as a physician and as a scientist, my focus is on understanding mechanisms critical for nociception in order to alleviate suffering of patients afflicted by “therapy-refractory” trigeminal pain. The agenda of my laboratory in the Duke Center for Translational Neuroscience is focused on understanding of nociceptive mechanisms. My lab employs a variety of methods in order to elucidate pain mechanisms. We use genetic model organisms, both mammalian and invertebrate (mouse and worm), and employ molecular biology tools.
At the molecular level, there are currently two areas of interest. First, going back to my initial discovery of the TRPV4 ion channel, published in Cell in October 2000, I do feel an affinity to further explore the function of TRPV4 in live animals, with a particular focus on nociception. The related C. elegans channel OSM-9 has been examined by a structure-function study in a live animal by a recent graduate student. There will be a sizeable number of highly exciting projects based on her findings and current concepts that have evolved from her work. However, in view of TRPV4’s demonstrated role in human TRPV4 “channelopathies”, human hereditary diseases as diverse as skeletal malformations and spinal muscle atrophies/ motor neuropathies, I am also aiming at elucidation of pathomechanisms of TRPV4 disease-causing mutations. In this respect, a highly rewarding collaboration has evolved with Dr. Farshid Guilak, Orthopedics Research at Duke.
Generally speaking, I strongly believe that a focus on innervating sensory neurons in dorsal root ganglion and trigeminal ganglion (expressing TRPV4) which interact with specifically innervated cells, will be a highly rewarding avenue to pursue. In regards to the innervated cells that feed back on the innervating sensory neurons, chondrocytes, a cell lineage which robustly expresses TRPV4, as well as epithelial cells in skin and airways are at the center of my particular interest. Focus on chondrocytes will bear relevance for joint pain as well as the TRPV4-channelopathy caused skeletal deformations. Airway epithelial cells are of relevance in chronic malignant and non-malignant human diseases such as COPD and chronic cough. In two well-visible publications, my group has been able to deconstruct COPD disease mechanisms in response to air pollution involving Ca++ influx via TRPV4, which is expressed in the ciliary brush border of such epithelia. Skin epithelia connect very closely with innervating nerve fibers forming the anatomic basis for somatosensory innervation of the skin.
The other process, at the molecular level, which my group is focusing on, is elucidation of gene regulation of the KCC2 chloride transporter gene. KCC2 (SLC12A5) is the dominant chloride extruding transporter molecule that dictates GABA-ergic neural transmission functioning either inhibitory or excitatory. We are particularly interested in transcriptional and chromatin-associated mechanisms that underlie the perinatal chloride shift, a drastic change that all vertebrate CNS neurons undergo around the time of birth from high to low chloride. I wish to establish a more complete understanding of transcriptional mechanisms that cause KCC2 up-regulation, based on our well-appreciated discovery of KCC2 gene repression by the REST complex acting on a dual-RE-1 DNA recognition element that brackets the transcriptional start site of KCC2 (forebrain isoform). In particular, I want to address the question whether reversal of developmental mechanisms of KCC2 gene regulation are causal for KCC2 down-regulation in the CNS in chronic pathological pain. An attractive view is that of chronic pathological pain as a literally vexing form of maladaptive neural plasticity which has a critical element of circuit hyperexcitability. In this view, circuit hyperexcitability would be caused by impaired extrusion of chloride from CNS neurons, such as in the spinal cord dorsal horn or the trigeminal spinal nucleus. Beyond pathological pain, neuronal chloride dysregulation is at the root of epilepsy, traumatic brain injury and possibly even neurodegenerative disease, so that molecular mechanisms of KCC2 gene regulation can be interrogated in these disease entities as well. Again, C. elegans could be recruited to study these mechanisms.
I foresee my two molecular foci of interest one day to merge at their common nexus, Ca++. For KCC2 gene regulation, we are exploring proactively the question which neuronal pathways and molecules that evoke increased intracellular Ca++ will trigger increased expression of KCC2. For the invertebrate functional orthologue of TRPV4, OSM-9, I intend to address the question what role OSM-9's Ca++ permeability plays in-vivo.