GENERATION OF MODELS FOR GENETIC HEARING LOSS

描述（由申请人提供）：本提案的最终目标是

DESCRIPTION (provided by applicant): The ultimate objective of this proposal is to create macaque models for the most prevalent types of hearing loss. Mutations in the gene for connexin 26 (GJB2) are the most common cause of hearing loss (DFNB1) in American and European populations, accounting for about 10% of all childhood hearing loss. An animal model is not available to study connexin 26 function in the ear because the mouse knockout is embryonic lethal. The expected outcome of this project, a macaque connexin 26 hearing loss model, will provide a foundation for important new clinical and basic studies of the most common type of inherited hearing loss. Our hypothesis, based on the carrier rate for the average recessive gene of about 1/100 in humans, is that generating a model for a recessive human disease by screening outbred primates will be easier than by targeted deletion of the gene in mice. Because mutations in GJB2 gene are the most common genetic cause of hearing loss, we have chosen this gene for our initial screen. The sequence is conserved between human and macaque with 18 base changes and 4 amino acid changes observed. We will test our hypothesis in a stepwise fashion by accomplishing the following Specific Aims. 1) Screen a large population of macaques for mutations in the GJB2 gene. Screening will be prioritized and putative mutation function will be evaluated based on our experience with human mutations. 2) Test the putative GJB2 homozygotes for phenotypic relevance. Once putative pathologic mutations are found, mating or in vitro fertilization at Regional Primate Centers will be arranged to produce homozygous offspring, and proposals will be submitted to study the phenotype and establish GJB2 macaque colonies. 3) Generate macaque models for additional hearing loss genes. Anatomical and physiological similarities between primates and humans have increased the importance of primate models. Responses of macaques to therapies will be similar to humans, increasing relevance of clinical studies. Basic hearing loss research in the macaque model will provide insights into pathologic mechanisms leading to hearing loss in humans. Understanding disease processes will be the basis for designing and testing new treatments that could reduce or prevent human inherited hearing loss.