Capita Foundation current funded projects:

"SANDBOX" (Simulated Activities of Naturalistic Disclosure) Co-principal investigators Kevin Franck Ph.D., and Joseph Donaher, Children's Hospital of Philadelphia.

The SANDBOX is a virtual reality, computer based program which will allow educators, parents and other interested parties to enter a realistic school-based setting while having a disability like stuttering or a hearing loss simulated electronically.  They will then be asked to maneuver through a set of activities similar to those routinely faced by children with disabilities.  In this way, the families and professionals may gain a heightened sense of the obstacles faced daily by the child and the inherent difficulty of incorporating rehabilitation strategies into everyday experiences.

This tool will also allow clinicians and children with disabilities to practice strategies or techniques in a safe virtual environment prior to trying them in the classroom. The SANDBOX program will also allow researchers to explore situations commonly experienced by children with developmental disabilities.  Thus, the Sandbox program is a powerful tool to increase carryover of new skills, to advance our knowledge base on developmental disabilities and to educate families and professionals.

Development of a Thin-Sheet Laser Illuminator for Optical Sectioning

Peter A. Santi Ph. D., University of Minnesota, Dept. of Otolaryngology.

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.

"Inhibition of apoptosis as a means to mitigate hearing loss in mice"

Alan M. Robinson Ph.D., Feinberg School of Medicine, Northwestern University, Dept. of Otolaryngology.

The mechanism of noise-induced damage to the cochlea resulting in hearing loss is not fully understood. However, cochlea damage via an apoptosis cell death pathway has been implicated, making inhibition of apoptosis following noise trauma a logical clinical target to reduce cochlea damage and hence preserve hearing. In order to determine to what specific apoptosis mechanism may be operating following noise-exposure we propose to determine if, and to what extent, mice that are genetically resistant to nerve cell apoptosis are protected? These mice are genetically modified transgenic mice that resist many triggers of apoptosis since they lack the Bax protein that is important in initiating the intrinsic apoptosis pathway. Identification of the importance of Bax may indicate a potentially useful site for pharmacological inhibition to prevent cochlea damage and
therefore hearing loss.  Related to this is the potential use of Minocycline, a common antibiotic that also has apoptosis-inhibiting properties as demonstrated in other cells. Following our interest in inhibiting apoptosis we performed a pilot experiment to inhibit noise-induced hearing loss in mice by administering Minocycline. The experiment provided evidence that administration of Minocycline significantly reduced the level of deafening following noise trauma. Further studies to establish the dose and effect relationship are necessary to identify the optimal dose giving maximal hearing
protection are required. The potential use of an established well-tolerated antibiotic to protect hearing before likely noise exposure or following noise trauma would be a significant clinical tool in hearing protection.

“High Resolution Imaging of the Cochlea in an x-Linked Alport Mouse Model”  Peter A. Santi Ph.D., University of Minnesota, Dept. of Otolaryngology.

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.