Avery Engelbrecht has been awarded a Doctoral Research Fellowship from the Myotonic Dystrophy Foundation (MDF). The goal of the MDF’s Research Fellows program is to provide adequate early career and ongoing funding in order to establish and drive a robust professional research community with a long-term commitment to the disease.
Avery is a predoctoral student in the UF Graduate Program in Biomedical Sciences (GPBMS) and works in Dr. Laura Ranum’s lab at the Center for NeuroGenetics. The focus of Avery’s fellowship will be on the characterization of a novel BAC transgenic mouse model of myotonic dystrophy type 2. This specialized mouse model was created using a large insert bacterial artificial chromosome (BAC) derived from human DM2 patient cells. The presence of large repeat expansions in the DM2 BAC mouse, and the fact that multiple lines of mice express the transgene provide strong promise that these mice will provide an important and physiologically relevant mouse model of DM2. This study will characterize novel DM2 mice generated by the Ranum lab in order to provide insight into the role of expansion RNAs and repeat associated non-ATG (RAN) proteins in the disease and hopefully to provide a DM2 mouse model that can be used to test therapeutic strategies.
This study is based upon considerable evidence gathered by the Ranum lab for the involvement of RAN proteins in myotonic dystrophy type 2 (see Zu et al, Neuron 2018). The DM2 repeat expansion expresses both sense (CCUG) and antisense (CAGG) expansion transcripts, which undergo RAN translation and result in the accumulation of toxic tetrapeptide sense (LPAC) and antisense (QAGR) RAN proteins in DM2 human autopsy brains. The presence of both RNA foci and RAN protein aggregates in the human patient tissue suggests both RNA gain of function effects and RAN proteins are likely to contribute to disease.
The support by the MDF for Avery’s project, which is entitled “Characterization of a Novel BAC Transgenic Mouse Model for DM2” , will enable the fully characterization of the molecular, physiological, and behavioral features of these DM2 BAC mice. Taken together, this work will characterize the first BAC transgenic mouse model of DM2, provide insight into the role of expansion RNAs and RAN proteins in DM2, and provide preclinical testing data on a potential therapeutic approach for DM2.