GENERATION OF MODELS FOR USHER SYNDROME

  • Kimberling, William J, (PI)

Project: Research project

Description

DESCRIPTION: Usher syndrome is an autosomal recessive disorder characterized by progressive retinitis pigmentosa (RP) and moderate to profound sensorineural hearing loss. It is the leading cause of combined deafness and blindness in the industrialized world, accounting for over half of the 20,000 deaf and blind people in the United States, and an additional 15,000-20,000 people with less severe hearing and vision loss. Mutations in the USH2A gene account for over half of Usher syndrome cases and approximately 10% of autosomal recessive RP, which affects approximately 67,000 people in the United States. Because gene functional differences lead to significant disparities in human vs. rodent retina function, mice and rats are incomplete models for RP. The expected outcome of this project, a macaque model for Usher syndrome, will be the foundation for important new clinical and basic studies. Our hypothesis, based on the carrier rate for the average recessive gene of 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. Because mutations in the USH2A gene are the most common genetic cause of RP, we have chosen this gene for our initial screen. 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 USH2A gene. Screening will be prioritized and putative mutation function will be evaluated based on our experience with human mutations. 2) Test the Putative USH2A Homozygotes for Phenotypic Relevance to Human Usher Ila.. 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 USH2A macaque colonies. 3) Generate macaque models for additional Usher syndrome genes. As the emphasis in human disease research shifts to trials of prostheses and treatments, anatomical and physiological similarities between primates and humans have increased their importance as models. Responses to therapies will be similar in macaques and humans, increasing the relevance of clinical studies. Basic research on retinal degeneration in the macaque model will provide insights into pathologic mechanisms leading to retinitis pigmentosa, which will be the basis for designing and testing new treatments that could reduce or prevent inherited blindness.
StatusFinished
Effective start/end date5/1/024/30/05

Funding

  • National Institutes of Health: $141,360.00
  • National Institutes of Health: $144,000.00
  • National Institutes of Health: $144,000.00

Fingerprint

Usher Syndromes
Macaca
Retinitis Pigmentosa
Mutation
Deaf-Blind Disorders
Primates
Genes
Recessive Genes
Retinal Degeneration
Sensorineural Hearing Loss
Gene Deletion
Homozygote
Fertilization in Vitro
Blindness
Research
Prostheses and Implants
Retina
Rodentia
Therapeutics
Phenotype

ASJC

  • Medicine(all)