Associate ProfessorOffice: R704(601) 984-1689 Lab: N630/N629; Phone: (601) 984-1663/984-1666 Fax: (601) 984-1655 Email: email@example.comWebsite
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:
While the olivocochlear system modulates auditory thresholds over the span of seconds to perhaps minutes, we hypothesized that the cochlea may also express a system that can act without the need for a delayed response from the brain (i.e. for a potentially damaging stimulus to be signaled to the brain and for the brain to then send back a signal indicating that a damaging stimulus has been encountered, during which time damage has already occurred), and through which longer lasting modifications to sensitivity may be elicited (i.e. if a potentially harmful environment is often encountered, sensitivity of the peripheral auditory system can be adjusted and held at the new baseline for extended periods). Our work along these lines has described the expression of the corticotropin releasing hormone related peptide urocortin in the cochlea, as well as the functional consequences resulting from ablation of the urocortin gene (Vetter et al., 2002). This work was the first to describe the expression of both a CRF-related peptide and the two CRF receptors in the cochlea. Results also demonstrated a role for urocortin in setting auditory sensitivity. As described above, we have most recently uncovered a system of peptides and G-protein coupled receptors expressed in the cochlea that are also part the well-known hypothalamic-pituitary-adrenal (HPA) axis (Graham et al., 2010; Graham and Vetter, 2011). The cochlear HPA-equivalent signaling system is wholly localized in the inner ear, and we hypothesize that it plays a role in modulating inner ear sensitivity over longer periods of time (minutes to hours). Supporting this hypothesis, we have gone on to use genetically manipulated mice carrying deletions of the two main CRF receptors to elucidate the mechanisms by which the CRF system functions in the inner ear. Our results demonstrate that activation of these receptors controls the sensitivity of the inner ear via coordinated affects on trafficking and expression of glutamate receptors, ATP receptors, and connexin subunits. Mutant mice lacking CRFR1 have decreased hearing sensitivity in addition to significant afferent innervation defects to the hair cells (Graham and Vetter, 2011). Interestingly, null ablation of CRFR2 results in a significant increase in hearing sensitivity, and a significantly greater susceptibility to noise-induced hearing loss occurs (Graham et al., 2010), demonstrating the extremely narrow operating point at which the inner ear normally functions in balancing sensitivity with susceptibility to acoustic injury. Thus far, work on the cochlear CRF system suggests that it serves to establish a balance of synaptic tone in the afferent auditory pathway. We next reasoned that if the CRF system is involved in setting sensitivity such that it is balanced with susceptibility to noise-induced hearing loss, it might also represent an endogenous system involved in general protection against various cellular stress events. Using a combination of standard biochemical assays and a mass spectrometry-based differential proteomics approach (Vetter et al., 2009), we have gone on to explore CRFR2 signaling in an in vitro model of cochlear derived cells to better define the changes that take place during drug-induced damage to cells of the inner ear. We showed that pre-activation of the cells with a CRFR2 specific agonist protects the cells from reactive oxygen species (ROS) generation, as well as superoxide dismutase (SOD) and caspase 3 (a cell death protein) activity. Following an in vitro proteomic analysis employing quantitative differential mass spectrometric procedures and iTRAQ labeling of the cells, we further detailed numerous differentially expressed proteins, many of which were not previously linked to cochlear function before (Basappa et al., 2010). Thus, the CRH system seems ripe for exploitation to generate novel interventional strategies against cell stress-related insults to the inner ear that result in hearing loss.
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
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