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Role of Protocadherins in hearing and deafness
The first project focuses on the mouse mutation Ames waltzer (av). The mouse av is a recessive mutation, which causes deafness and vestibular dysfunction associated with degeneration of the inner ear neuroepithelia. The gene that harbors the av mutation was identified as a protocadherin, Pcdh15. Subsequent work showed that mutation in the human homologue of the mouse Pcdh15 causes Usher syndrome type 1F, establishing the av mouse as a model for deafness in USH1F. Using the mouse model, we are trying to uncover the role of Pcdh15 in the normal development of hearing function.
The second project focuses on the identification of other Protocadherins genes that may be important for the normal development and maintenance of hearing function. Since the identification of Pcdh15 and its role in hearing, we have been interested in other protocadherins. Reports from other labs show that mutations in other protocadherins, such as Cdh23, cause deafness in mice and humans. Taken together these data suggests that other protocadherins may be critical to the development of inner ear neuroepithelia and hearing function. There are about 70 protocadherins, many of which are expressed in the CNS. The function and expression pattern of many of these 70 protocadherins are unknown. A variety of methods including DNA sequence comparison, cochlear expression database searches, and expression analysis of cells within function domains of the cochlea are being used to determine protocadherin genes that may be important for hearing.
Personnel involved:
PI: Kumar Alagramam, Ph.D.
Research Assistant: Daniel Chen, M.S.
Research Assistant: Lauren Kisley, B.S.
Collaborators:
Karen Pawlowski, Ph.D. UTSW, Dallas
Charles Wright, Ph.D. UTSW, Dallas
Understanding the molecular pathogenesis of Meniere’s Disease
The goal for this project is to better understand the molecular biological changes that occur in the inner ear as a result of endolymphatic hydrops, a condition known to accompany Meniere’s disease, a disorder associated with hearing loss and vertigo. Although it has been shown that vertigo can be controlled by numerous medical and surgical interventions, the hearing loss and subsequent deafness have no known treatment. Our studies are done using a well-known model of surgically induced endolymphatic hydrops in the guinea pig. Once hydrops has been established, inner ear tissue samples will be collected and subjected to molecular biological techniques that allow for determination of whether messenger RNA levels of genes critical to EAA physiology are up-regulated or down-regulated. This will provide clues to better understand the exact biochemical pathways that are activated in this condition and possibly provide for new treatment strategies. It is expected that this project will lead to a larger grant in the future which will allow us to explore and define the entire cascade of biochemical changes which accompany Meniere-related endolymphatic hydrops and could lead to better treatment alternatives for patients with Meniere-related hearing loss.
Personnel involved:
PI: Cliff Megerian, M.D.
Co-PI: Kumar Alagramam, Ph.D.
Research Assistant: Lauren Kisley, B.S.
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