The long-term goal of this project is to establish a series of nonhuman primate models for the investigation of human visual system disorders. Currently, the mouse is the predominant model system used in this field, largely due to our ability to generate genetically engineered animals for the study of specific diseases. However, despite their similarities with humans, mice and other rodents do not have a cone-rich macula, the region most critical for human vision. Therefore, a nonhuman primate (NHP) model system that more closely matches human will offer important new insights into disease processes and provide much improved opportunities for development and testing of novel treatments or preventions for specific eye diseases. Our initial sequencing results from ~200 rhesus macaques (Macaca mulatta) indicate that the genetic diversity among macaques is much greater than among people. Among the macaques, we found many individuals carrying pathogenic mutations in known human retinal disease genes. Therefore, the macaque model represents a golden but currently untapped opportunity for innovative research. It is feasible to leverage existing infrastructure to generate a wide range of novel primate models (breeding lines with informative mutations) that will be invaluable for research concerning pathogenesis and the development of treatments. To demonstrate the feasibility of this approach and begin exploiting its potential, we propose to:
Aim 1. Perform targeted sequencing of retinal disease genes in 1,600 individual rhesus macaques.
Aim 2. Establish a mutational database for macaque eye genes.
Aim 3. Generate multiple macaque models of human eye diseases.
Aim 4. Characterize the phenotypes produced and begin testing of treatments of macaque models

Public Health Relevance

The long-term goal of this project is to establish a series of nonhuman primate models for the investigation of human visual system disorders. Leveraging existing infrastructure, a large database containing genotype results from 1,600 rhesus macaques for human retinal disease genes will be established. Furthermore, multiple novel primate models that mimic human visual disorders will be generated, which will be invaluable for research concerning pathogenesis and the development of treatments.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY026045-04
Application #
9689454
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Shen, Grace L
Project Start
2016-03-01
Project End
2021-02-28
Budget Start
2019-03-01
Budget End
2020-02-29
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Xue, Cheng; Raveendran, Muthuswamy; Harris, R Alan et al. (2016) The population genomics of rhesus macaques (Macaca mulatta) based on whole-genome sequences. Genome Res 26:1651-1662