Michael Anne Gratton, PhD
Specialties and Subspecialties
Auditory Research Lab M122 Schwitalla Hall
1) Matrix Otopathology: The Gratton lab is interested in mechanisms controlling inner ear homeostasis. The focus of our studies is the relationship of basement membrane to inner ear function and hearing. During development of the inner ear, basement membranes play a critical role in cell migration and differentiation. The role of cochlear basement membranes in the adult ear is unknown. In other mature tissues, basement membranes are involved in cell adhesion and polarization as well as tissue permeability. Alport syndrome is a genetic basement membrane disease of the kidney, ear and eye. We use the mouse model of Alport syndrome to study basement membrane function in the adult inner ear. In the Alport mouse, the basement membranes surrounding blood vessels of the stria vascularis, a tissue in the inner ea, become grossly thickened. The expression of genes and proteins controlling basement membrane synthesis and degradation are being quantified in the Alport mouse while cationic probes are being used to determine if blood vessel permeability has been altered. The electrochemical and transport properties of the Alport stria following noise exposure to deplete strial energy production are being explored.
2) Potassium Homeostasis: A unique transmembrane potential, termed the endocochlear potential (EP) (> 80 mV), is a requisite for normal sound transduction. The mechanisms generating and maintaining this inner ear potential have not been entirely elucidated. Several selective and nonselective ion channels, both voltage-gated and non-voltage-gated, and some novel to the inner ear, have been found in the cochlear lateral wall tissues responsible for the EP. These channels serve to create a high throughput of potassium across the cells and apical membrane of the stria vascularis. In collaboration with Ebenezer Yamoah at UC-Davis, we seek to characterize the specific functions of recently identified K+ and Cl- channels, and determine how they work together to mediate the EP. My role in this collaboration is the localization of the channel proteins in inner ear tissues, specifically those of the inner ear lateral wall. Immunohistochemistry is used to identify tissues that express the protein of interest in normal and mutant mice at the light microscope level. Further characterization of the protein at the cellular and subcellular level employs immuno-electron microscopy. Dual visual labels are used to help determine whether channel subtypes form functional units.
3) Gene therapy for Usher Syndrome 1C: The longterm goal of this research is to develop gene therapy approaches that can be used successfully in vivo to slow or prevent deafness and blindness in Usher Syndrome. USH1C, an autosomal recessive form of the disease, is the focus of our studies since: 1) it accounts for a significant percentage of USH1 disease (12.5%) and 2) the USH1C gene, which encodes harmonin can, when mutated, result in other (non-syndromic) inherited forms of congenital deafness. In collaboration with Jean Bennett at the University of Pennsylvania, we use a retroviral package to deliver genes to the developing cochlea and then and test therapeutic effects of the wildtype harmonin gene in the neonatal pup. In parallel, an additional Ush1c knockin mouse model is being characterized in detail in order to further define pathogenic mechanisms leading to deafness and blindness in USH1C. My role in this preject is primarily the assessment of the success of gene therapy in returning cochlear function.