Research | Raphael Lab
Lab Overview
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. Specific projects are discussed in more detail below.
Loss of sensory cells (hair cells) in the inner ear leads to hearing loss. Once lost, auditory (hearing) hair cells in humans and other mammals do not regenerate, which is why inner ear deafness (sensorineural deafness) is permanent.
We are designing new tools and approaches to regenerate hair cells in ears that are depleted of their original hair cells. The main strategy is to test over-expression of genes that regulate hair cell development during embryonic stages for their ability to generate new hair cells in mature deaf ears.
The technology used for this purpose is gene transfer which is accomplished by viruses that can shuttle genes into the target cells. The target cells are non-sensory cells (supporting cells) that remain in deaf ears after hair cells degenerate. Outcomes are measured using histological and physiological assays. Work is done in collaboration with Andrew Groves, PhD and Washington University, St. Louis.
Epigenetic regulation of gene expression occurs via heritable changes in DNA and associated histone proteins. Such modifications, which include methylation, acetylation, and nucleosome repositioning, have a major and poorly understood role in development and disease. Recent studies have begun to explore epigenetics of hearing and balance disorders which negatively impact quality of life and impose a significant socioeconomic burden on millions of Americans.
The chromodomain helicase DNA binding protein 7 (CHD7) is an ATP dependent epigenetic chromatin remodeler implicated in inner ear development. Mutations in CHD7 cause CHARGE syndrome, which involves hearing and balance deficiencies. We are testing histological and functional outcomes of mutations leading to reduced levels of CHD7 expression in mouse models of CHARGE. The leading laboratory of this project is directed by Donna Martin, MD, PhD here at Michigan Medicine.
Sensorineural hearing loss is highly prevalent in military Veterans, but there is currently no biological treatment enabling full restoration of the cochlea and hearing perception. Hearing restoration by stem cell therapy holds great promise. We are focused on stem cell therapy for the severely damaged cochlea, where extreme or chronic injury has reduced the organ of Corti to a flat epithelium of stromal cells that have so far proven refractory to genetic approaches to regeneration. This approach may be the only viable strategy for restoring the full sensory epithelium in older veterans with long-term hearing loss.
In this project, we test the hypothesis that multipotent otic progenitors will be required to replace both hair cells and supporting cells in the severely damaged cochlea. The proposal tests the impact of implanting donor cells at various stages of differentiation and examines the role of the extracellular matrix in promoting donor cell survival and maturation. Our data should open new paths toward a viable biological treatment for severe hearing loss. This is a collaborative project with the laboratory of Keith Duncan, PhD here at Michigan.
- Characterization of Usher Syndrome Type 3a (Ush3a) using a rabbit gene editing model, and development of therapies using gene transfer.
- Using AAV gene therapy to treat GJB2 deafness using a CX26 mouse model.
