Characterizing a Conditional Transgenic Mouse Model of FSHD

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DESCRIPTION (provided by applicant): Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant muscle disorder caused by complex genetic and molecular mechanisms. Recent discoveries improved our understanding of the genetic cause of FSHD and allowed us to focus our efforts on the aberrantly expressed DUX4 in FSHD. Knocking down the DUX4 protein in FSHD is an acute area of research since it is directly relevant to disease treatment. A suitable DUX4 model will provide a critical tool for such studies. Generating a suitable animal model for studying FSHD has been extremely challenging due to the cytotoxic nature of the DUX4 when it is ectopically expressed. To overcome this obstacle, we generated a tetracycline-repressible (tet-off) DUX4 transgenic mouse model. In this mouse model, the expression of DUX4 is controlled by oral doxycycline. The DUX4 transgene is suppressed when the mice receive oral doxycycline from their drinking water. Using this system, the expression of DUX4 can be induced at a desired time and the expression is restricted to skeletal muscles when the mouse is cross-bred with a mCK-tTA mouse line. In aim 1 of this application, we will characterize the phenotypes of the tet- repressible muscle-specific DUX4 transgenic mice (TRE-DUX4/mCK-tTA) and determine the effects of the duration of expression and the age of mice on the phenotypes. In aim 2, we will determine whether the phenotypes developed in response to the DUX4 expression is reversible. The main goal of this application is to characterize the mouse model and to determine whether the DUX4 model recapitulates the human disease at the physiological, histopathological and molecular level. If proven to be a suitable model for investigating FSHD mechanisms, testing therapeutic means or both, this DUX4 model will have a high impact to the field of FSHD research.