In general, my research interests include the mechanisms by which synapses form and undergo structural plasticity, what role early maturational processes such as peripheral spontaneous activity play in setting up mature CNS pathways, and mechanisms underlying endogenous systems of protection involved in maintaining synapses in the face of challenge (metabolic, physical injury, etc.). More specifically, my interests lie in understanding:
Our work investigates mechanisms (gene expression and cell signaling cascades) by which descending neural input to hair cells and local peptide-based paracrine signaling regulates the afferent and efferent synaptic structure and strength within the mammalian cochlea. The immediate goals of our current research are three-fold. First, we seek to provide a framework useful for understanding the mechanisms by which synapse formation occurs in the auditory periphery. This determines the nature of the initial information flow to the central auditory regions of the brain. Second, we seek to define the molecular mechanisms by which hearing sensitivity and susceptibility to noise-induced and ototoxin-induced hearing loss is set and modulated. While it is well recognized that sensitivity can be modulated over a timeframe of seconds (via classic efferent actions having their origin from lower auditory brainstem centers), we hypothesize that this can also occur over the course of hours to days, and function in a proactive, protective manner to shield hair cells from damage. We hypothesize that this type of protection originates from local (paracrine) activity involving the corticotropin-releasing factor (CRF) signaling system we have recently identified. Finally, we ask how normal and abnormal peripheral states feed into CNS auditory systems during development to modulate synaptic (structural and functional) plasticity of central auditory centers. Defects in CNS processing can alter sub-cortical based abilities such as localization of sound in space, to higher-level cognitive abilities of speech perception as well as disease states such as tinnitus. Our work toward these goals can be split into two complementary trajectories. First, we and colleagues previously discovered that nicotinic acetylcholine receptor (nAChR) activity modifies CNS derived neural innervation and synaptic terminal structure in the cochlea, and went on to describe the mechanisms by which this modulation is established. We have also used the Affymetrix gene chip-based gene expression system to define the changes to global gene expression following manipulations of the hair cell expressed nAChRs and found a delayed developmental state of the cochlea following silencing of nAChR activity. Secondly, we have discovered a local signaling system within the cochlea that is molecularly equivalent to the classic hypothalamic-pituitary-adrenal axis stress-response system composed of CRF and its receptors, along with pro-opiomelanocortin (POMC), adenocorticotropic hormone (ACTH), and the ACTH receptor melanocortin 2 receptor (MC2R). We have elucidated how CRF and a related peptide, urocortin, and their receptors participate in setting basal hearing sensitivity, and how the system modulates susceptibility to acoustically mediated trauma. In a related line of work, we have begun to use quantitative mass spectrometry (specifically iTRAQ labeling) to examine the proteomic response of inner ear derived cells following presentation of ototoxic drugs. Each research line is briefly presented below.
While our main research focus includes the inner ear, we address many basic neuroscience problems from a cell and molecular biology approach that are related to the role specific genes and proteins play in cell signaling and plasticity of neurotransmission, neuronal circuitry development, and pathological states. We are also poised to move aspects of our work back to investigating central auditory system function in some of our mutant lines, especially concerning the impact of early neural activity on the development and function of central auditory circuitry. I believe one of the strengths of our lab is that we integrate numerous techniques from classical morphological and physiological analyses to cutting edge molecular and genetic/proteomic techniques to address problems of interest.
*In last four years