Project (#1) Name: "Development of a Thin-Sheet Laser Illuminator for Optical Sectioning"

Project (#2) Name: "High Resolution Imaging of the Cochlea in an x-Linked Alport Mouse Model"

Location: University of Minnesota, Dept. of Otolaryngology

view the .PDF file for additional information on the research for Project #2.

Peter A. Santi, Ph.D.

Project (#1) Name: "Development of a Thin-Sheet Laser Illuminator for Optical Sectioning"

The goal of this research is to develop a new, high resolution, laser illuminator that would optically section relatively thick (mm-cm) tissues. This new device (thin-sheet laser illuminator) will allow investigators to image whole tissues at high resolution, and is compatible with selective, fluorochrome-labeling of tissues structures. This device will efficiently produce a stack of well-aligned images for three-dimensional (3D) reconstruction of tissue structures in order to provide a better understanding of structure/function relationships within a complex sensory organ such as the cochlea. Development of this device will enable other investigators to optically section a wide range of large tissues (e.g., eye, heart, kidney, bones...) and due to its low cost and flexibility, it can be used in individual and service laboratories and fitted to a wide range of microscopes.

Project (#2) Name: "High Resolution Imaging of the Cochlea in an x-Linked Alport Mouse Model"

Alport syndrome is a progressive, hereditary disorder of basement membranes which includes deafness, progressive glomerulopathy, and end-stage kidney disease (Kastan, 2002). X-linked Alport syndrome is caused by mutations in the COL4A5 gene and comprises 80% of all known cases. 100% of males with this gene are affected; whereas, female carriers show a more benign course of the disease. This mutation results in the lack of the production of novel (alpha 3,4,5 type IV collagen chains), and in the kidney, lack of these novel chains results in splitting and fragmentation of the glomerular basement membrane and kidney failure. We have previously described (Kleppel et al.,1989ab) the presence of novel type IV collagen chains in the basement membrane of the basilar membrane in cochleas in normal humans. More recently, we have also described pathological changes in temporal bones from humans with Alport syndrome (Merchant et al., 2004), and the lack of novel type IV collagen chains in their basement membranes (Zhender et al., 2005). We proposed that these "zones of separation" are due to the lack of the novel chains in certain cochlear basement membranes and are the cause of the progressive, sensorineural hearing loss observed in Alport patients. Recently, and X-linked mouse model of Alport syndrome has been developed here at the University of Minnesota (Rheault et al., 2004), and Dr. Segal has generously agreed to provide us with these animals. Although kidney degeneration patterns have shown in this animal model, cochlear pathologies have not yet been investigated. I propose to examine cochleas from this animal model and to determine if basilar membrane defects are present which are similar to those that we deschribed in cochleas from humans with Alport syndrome. This research should provide important information on the pathophysiological mechanisms of hearing loss in Alport syndrome, facilitate future funding opportunities, and promote gene therapy studies for inner ear diseases, which would cure this disease and its hering loss in humans.

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