The present proposal intends to establish as a proof in concept the feasibility of a transgenic model of inherited neurodegenerative disease in the nonhuman primate (NHP). For several reasons delineated below, we will focus initially on a model of Huntington's Disease (HD), an autosomal dominant neurodegenerative disorder resulting from a mutation of the huntingtin (htt) gene found on chromosome 4. Neurodegenerative diseases are complex disorders that involve neuropathological and psychiatric alterations. Although transgenic and knock-in mouse models of HD have been created, limited representation in clinical aspects have been reported and the rodent models lack true neurodegeneration. Chemical induction of HD in NHP (nonhuman primates) has been reported, but the role of intrinsic genetic factors in the development of the disease is not possible to determine. For this proposal we will focus on Huntington's Disease (HD) where the genetic defect has been identified. The overall goal of this project is to develop a transgenic nonhuman primate (NHP) model for HD. Due to genetic and behavioral similarities between human and NHP, a transgenic NHP carrying a HD mutant gene similar to that of patients will help to clarify our understanding of the disease onset and its development. Additionally, monitoring HD onset and development in transgenic NHP by high resolution brain imaging technology such as MRI, and behavioral and cognitive testing can all be carried out simultaneously in NHP but not in other animal models. Moreover, because of the similarity in motor repertoire between NHPs and humans, it will be also possible to compare the neurological syndrome observed in the NHP model to the neurology in HD patients. Understanding the correlation between genetic defects and physiological changes (e.g. oxidative damage) will lead to a better understanding of disease development, the development of patient treatments and medications and importantly the development of preventative approaches for high risk individuals. We have successfully created the first transgenic NHP """"""""ANDi"""""""". The impact of transgenic NHP of HD in understanding genetics disorder and its role in the development of efficacious intervention approaches and medications is also recognized. Here, we propose to develop a transgenic NHP model of HD and their role in understanding of human genetic disorders will be evaluated. In order to accomplish our goals, three specific aims are proposed: (1) the development of retroviral and lentiviral vector for producing transgenic NHP, (2) the development of a transgenic NHP for HD, and (3) the assessment of phenotype of the transgenic HD-NHP model.
Showing the most recent 10 out of 29 publications
