Model of OPMD with constitutive PABPN1 expression

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Oculopharyngeal muscular dystrophy (OPMD) is caused by expansion of a short GCG repeat in the gene encoding the nuclear polyadenylate binding protein, PABPN1. The GCG repeat is translated as a short tract of alanines. The wild-type allele encodes 10 consecutive alanine residues at the N terminus of PABPN1. Dominantly-inherited OPMD results when this polyalanine tract has at least 12, but not more than 17 alanines. Evidence supports a model in which aggregation of the mutant PABPN1 protein leads to muscle degeneration. The mutant protein forms nuclear inclusions in skeletal muscle. In many protein conformation diseases, such as, polyglutamine diseases, aggregation of mutant protein leads to neuronal degeneration, even though the mutant proteins are widely expressed in non-neural tissues. By contrast, OPMD is the first example of a protein conformation disease, involving a gene that is probably expressed in all mammalian cells, that appears to selectively affect skeletal muscle. However, the respective contribution or neural versus muscle degeneration to the phenotype is presently uncertain, and the conventional view that OPMD is exclusively a disease of skeletal muscle has been recently challenged. Animal models are needed to study the pathophysiology and treatment of this disorder. Several transgenic models have been developed, but they have limitations, and there still is a need for a model that reproduces the phenotype and the natural pattern of PABPN1 expression. The aim of this proposal is to develop and characterize a transgenic mouse model in which the expression of mutant PABPN1 is controlled by the natural regulatory elements from the PABPN1 gene. We have developed a construct in which potential autoregulatory mechanisms for restraining PABPN1 expression are disabled, so that transcription from the PABPN1 promoter can support a higher level of protein expression. These modifications should enhance the pathogenicity of the mutant allele. We plan to develop lines of transgenic mice expressing the mutant or wild-type PABPN1 protein, and carry out an initial analysis of the phenotype. These lines of transgenic mice will be useful to study this novel mechanism for muscle degeneration, and they also may provide insight into the general pathophysiology of protein conformation diseases. Furthermore, there are indications that this form of muscular dystrophy is particularly amenable to therapeutic intervention. By developing a mouse model that is valid for preclinical studies, results from this project will lay the groundwork for developing effective treatments.