Raphael Laboratory

Research in the Raphael lab is dedicated to protection, repair and regeneration of sensory hair cells and neurons in the inner ear.  We are exploring novel treatments for loss of hearing and balance due to aging, ototoxic trauma and genetic inner ear disease.  The therapies we develop utilize both gene therapy and pharmacological approaches.  We are also exploring ways to enhance the health the neural substrate in the deaf cochlea in order to improve cochlear implant function.  Specific projects are discussed in more detail below.

Genetic Hearing Loss

Deafness caused by genetic factors can be congenital or late onset progressive, affecting us as we age, and leading to social isolation and professional limitations. Genetic deafness may result from mutations in any one of a large number of genes. Syndromic and nonsyndromic genes that cause deafness when mutated have been identified in recent years. Knowledge of the role of these genes in the development, function and/or pathology of the inner ear is important for developing diagnostic tools, preventive and therapeutic measures and for increasing the general understanding of inner ear biology. Our current work is focused on two specific deafness genes, Chd7 and Gjb2.

CHARGE Syndrome, affecting 1 in 10,000 newborns, is a multiple disorder sensory second only to Usher Syndrome as a cause of deafblindness.  CHARGE is caused by heterozygous mutations in the CHD7 gene encoding a DNA binding ATP-dependent chromatin remodeling protein.  In collaboration with Donna Martin and her group at Michigan, we study mouse models of CHARGE Syndrome. We observed a significant overlap in phenotypes between CHARGE Syndrome, retinoic acid embryopathy, and vitamin A deficiency.  We are using the mice for better characterizing the distribution and roles of CHD7 in the developing ear and for designing biological therapies for ameliorating hearing and balance deficits in individuals with CHARGE Syndrome.

The most common form of autosomal recessive hereditary deafness is due to loss of the Connexin 26 (Cx26) protein (encoded by the human GJB2 gene).  Mouse models for reduced Cx26 exhibit many of the features found in humans with Gjb2 mutations. Together with Karen Avraham and her group at Tel Aviv we generated and characterized a mouse in which Cre, driven by the promoter of the supporting cell gene Sox10, deletes Gjb2 from supporting cells.  In collaboration with Donna Martin and her group at Michigan, we are using this mouse, Sox10Cre-Gjb2, in experiments designed to improve understanding of the pathophysiology of Gjb2 mutations in the ear, and to accelerate development of specific and effective gene-based therapies for human Cx26 related deafness. 

 Hair Cell Replacement Therapy

The most common form of hearing loss is caused by the death of hair cells in the cochlea. Many animals such as birds, frogs and fish, are capable of regenerating their hair cells, but mature mammals are unable to regenerate their cochlear hair cells. We and others have shown the over-expression of developmental genes in non-sensory cells can produce new sensory cells. This approach is inefficient in mature animals. Our studies are aiming to characterize changes in chromatin in supporting cells and find ways to reverse them in order to increase the number of new hair cells generated with over-expression of developmental genes such as Atoh1. This work is being performed in collaboration with Andy Groves and his team at Baylor. 

Stem cell transplantation is another avenue for cell replacement. Stem cell technology provides a useful research tool with basic science and clinical applications.  Replacing lost hair cells by implantation of stem cells in the cochlea is a complicated task due to the hostile ionic environment in the cochlear fluid.  We have designed methods for transiently changing the ionic environment and were successful in implanting stem cells into the cochlea.  Our current experiments are to design better sources for stem cells, work done in collaboration with Keith Duncan and his group at Michigan, and to determine how to differentiate these implanted stem cells into the desired types of therapeutic cells in the cochlea.

 Improve Hearing with the Use of the Cochlear Implant

Cochlear implant auditory prostheses have been remarkably successful in restoring communication abilities to hearing impaired people but there is still large variability in performance among patients, likely due in part to the conditions in the cochlea near the implanted electrodes. In collaboration with Bryan Pfingst and his team at Michigan, we are using tissue engineering technologies to preserve or restore neural and/or sensory elements in the implanted cochlea and test the outcomes on function of the cochlear implant.  Important biological goals include enhancing neurite sprouting, increasing survival of auditory neurons, and reducing growth of connective tissue in the cochlea.