Translation and Human Diseases

The role of the CACNA1A transcription factor, a1ACT, in normal development. Xiaofei Du, MD, Research Associate Professor.  

We are studying in detail the behavioral, electrophysiological, genetic effects of a1ACT in normal mouse development.  We show that this protein rescues mice with abnormal calcium channel function.  This protein appears to play a key role in the early maturation of the neonatal and juvenile cerebellum, but may be dispensable in adult life.  This finding would be key for therapeutic strategy of suppressing a1ACT to treat SCA6.

The pathogenesis of SCA6. Xiaofei Du, MD, Research Associate Professor.

We are exploring the disease mechanisms active in SCA6 by investigating the effect of SCA6 mutation in a1ACT on the protein binding partners and the gene targets of a1ACT.  We are performing structure-function studies of a1ACT to investigate the key requirements for toxicity of this disease protein.  We are developing novel chromic models of SCA6 that express a1ACT under control of the IRES.

The search for other bicistronic calcium channel genes. Eshaan Rao, PhD candidate in Neurobiology.

There are a total of 10 members of the voltage-gated calcium channel gene family.  We are accumulating growing evidence that many more gene members of this family are bicistronic and produce a calcium channel and a transcription factor.  We plan to characterize the behavior and gene targets of these novel calcium channel-coupled transcription factors and to explore their roles In neuronal development and neurological disease.  We expect that this work will open up many new basic projects for other trainees.

Regulation of IRES in calcium channel genes.  Jack Godfrey, PhD, post-doctoral fellow.

Using a series of bait-prey pull-down techniques we are attempting to characterize the molecular regulation of the Independent translation process that occurs at the CACNA1A IRES.  We anticipate that the regulation of this IRES could include both RNA molecules and RNA binding proteins.  Insights into this regulation could have vast implications in developing treatments for a wide array of neurological diseases and cancer.

The search for other bicistronic cellular genes (HER2). Jack Godfrey, PhD, post-doctoral fellow. 

HER2 is a transmembrane receptor tyrosine kinase which is frequently amplified in breast cancer.  The monoclonal antibody Herceptin is a targeted treatment for HER2 amplified breast cancer with proven clinical efficacy.  Unfortunately, HER2 amplified tumours may develop resistance to Herceptin through a number of mechanism, one of which involves expression of a truncated HER2 protein (HER2Δ95) which lacks the Herceptin epitope. Previous studies have shown that HER2Δ95 is produced bicistronically. We are currently we are currently investigating whether we can take advantage of this bicistronic expression mechanism to treat these cancers.

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