This proposal has evolved based on our recent success in developing transgenic Huntington's disease nonhuman primates (HD-NHPs). Longitudinal study on HD-NHPs demonstrated the progressive development of clinical features similar to HD patients using clinical measurements similar to humans. Cognitive behavioral decline, neural anatomical changes, alterations of genome and metabolite profiles as disease progresses strongly suggested the potential application of HD-NHPs as a pre-clinical animal model for studying neurodegeneration, HD pathogenesis and the development of novel therapeutics. In order to make this novel animal model available for the research community, an HD-NHP resource that will serve as a hub for facilitating the applications of the HD-NHP model by providing characterized HD-NHPs and longitudinal biomaterials for investigators will be established. The overall goal of this application is to establish a Transgenic Huntington's Disease Monkey Resource (THDMR). This resource will meet the needs of the biomedical research community by establishing the infrastructure for generating high quality, well-characterized HD-NHPs for collaborative research to generate new information which will benefit the HD and neurodegeneration scientific community. To accomplish our goal, we will establish a small breeding colony for the production of a small number young HD-NHPs that will be readily available for investigators. We plan to start with a small-scale production, but with th capacity for quick expansion with the aid of assisted reproductive techniques that are well established in PI's laboratory. Biomaterial repositories including peripheral blood samples, cell culture and sperm cryobank will also be established. To further facilitate translational applicatio of this novel model, our goal is to overcome the current key, limiting factor, which is their availability. We will develop and optimize sperm cryopreservation methods to safeguard future production and preserve the unique genetics of the HD-NHPs so that frozen semen could also be efficiently distributed to primate centers worldwide to produce HD-NHPs for use by investigators. It is an exciting time for neuroscience research and modeling of human inherited genetic diseases using transgenic NHP.
The Specific Aims for the proposal are:
Aim 1. To establish a breeding colony and provide F1 HD-NHPs with essential characterization that readies them for preclinical research, Aim 2. To establish a HD-NHP biomaterial repository and Aim 3. To optimize the cryopreservation method of HD-NHP sperm and the establishment of sperm cryobank.

Public Health Relevance

The proposed study has evolved based on our success in the creation of a transgenic Huntington's disease (HD) monkey model sponsored by the ORIP that recapitulate disease progression and develop clinical features similar to HD patients. In order to facilitate the preclinical application of the HD monkey model, a Transgenic Huntington's Disease Monkey Resource (THDMR) will be established to provide a high quality HD monkey model and longitudinal biomaterials for investigators. To further safeguard the unique genetics of the HD-NHPs and availability of the HD-NHPs, HD sperm cryopreservation methods will be developed and optimized, and frozen sperm will be deposited and distributed through the sperm cryobank for reanimation of the HD monkeys.

Agency
National Institute of Health (NIH)
Institute
Office of The Director, National Institutes of Health (OD)
Type
Resource-Related Research Projects (R24)
Project #
2R24OD010930-10A1
Application #
8855837
Study Section
Special Emphasis Panel (ZRG1-BBBP-Y (45))
Program Officer
Harding, John D
Project Start
2003-12-01
Project End
2018-12-31
Budget Start
2015-03-01
Budget End
2015-12-31
Support Year
10
Fiscal Year
2015
Total Cost
$837,152
Indirect Cost
$337,375
Name
Emory University
Department
Genetics
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Snyder, Brooke R; Chan, Anthony W S (2018) Progress in developing transgenic monkey model for Huntington's disease. J Neural Transm (Vienna) 125:401-417
Hunter, Carissa E; Pongos, Alvince L; Chi, Tim Y et al. (2018) Longitudinal Anthropometric Assessment of Rhesus Macaque (Macaca mulatta) Model of Huntington Disease. Comp Med 68:163-167
Meng, Yuguang; Jiang, Jie; Bachevalier, Jocelyne et al. (2017) Developmental Whole Brain White Matter Alterations in Transgenic Huntington's Disease Monkey. Sci Rep 7:379
Kunkanjanawan, Tanut; Carter, Richard; Ahn, Kwan-Sung et al. (2017) Induced Pluripotent HD Monkey Stem Cells Derived Neural Cells for Drug Discovery. SLAS Discov 22:696-705
Kunkanjanawan, Tanut; Carter, Richard L; Prucha, Melinda S et al. (2016) miR-196a Ameliorates Cytotoxicity and Cellular Phenotype in Transgenic Huntington's Disease Monkey Neural Cells. PLoS One 11:e0162788
Raper, Jessica; Bosinger, Steven; Johnson, Zachary et al. (2016) Increased irritability, anxiety, and immune reactivity in transgenic Huntington's disease monkeys. Brain Behav Immun 58:181-190
Moran, Sean; Chi, Tim; Prucha, Melinda S et al. (2015) Germline transmission in transgenic Huntington's disease monkeys. Theriogenology 84:277-85
Chan, Anthony W S; Jiang, Jie; Chen, Yiju et al. (2015) Progressive cognitive deficit, motor impairment and striatal pathology in a transgenic Huntington disease monkey model from infancy to adulthood. PLoS One 10:e0122335
Kocerha, Jannet; Xu, Yan; Prucha, Melinda S et al. (2014) microRNA-128a dysregulation in transgenic Huntington's disease monkeys. Mol Brain 7:46
Chen, Yiju; Carter, Richard L; Cho, In K et al. (2014) Cell-based therapies for Huntington's disease. Drug Discov Today 19:980-4

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