Investigating Ddr2 gene downregulation as a novel therapeutic target for PSP and related tauopathies

Pipeline Grant

Principal Investigator: Dr. Yuhao (Harry) Min, Mayo Clinic Jacksonville

Progressive supranuclear palsy, or PSP, is a brain disease marked by movement difficulties that rapidly deteriorate, leading to death. Many efforts were made to develop a drug to treat PSP, but none succeeded, leaving no cure for this relentless disease. Scientists in our laboratory previously identified several genes involved in PSP, one of which is called DDR2. Our team manipulated DDR2 in fruit fly models of PSP and was able to slow or even stop the devastating pathological process seen in PSP. Therefore, we believe that the gene DDR2 can be targeted to develop a future therapy to slow and stop the progression of PSP. However, experiments performed in fruit flies may not relate to the complex human brain. Therefore, additional studies using a more relevant model of PSP are needed before we can confidently move the discovery into clinical trials.

To achieve this, we will use an animal model that develops PSP-like pathology in their brains. We plan to manipulate DDR2 in this animal model. We will check if the manipulation is safe and if it leads to favorable outcomes. Additionally, we want to understand why and how the manipulation works. We will incorporate RNA sequencing (RNAseq) technology to measure all RNA molecules. RNAseq technology can be helpful because RNA molecules carry the instructions for biological activities. By measuring RNA, we can detect the changes related to DDR2 manipulation. This information will help us elucidate the potential mechanism(s) of action and find biomarkers to monitor the treatment in future experiments. Together, the proposed work will add important knowledge and provide pivotal evidence for using DDR2 as a novel target to treat PSP. Our work will contribute to the overall drug development effort for PSP and hopefully bring an effective treatment for PSP patients.