Towards A Knockdown Therapy For Tauopathy
We propose to do research using genetically modified mice carrying P301L mutation, a genetic alteration associated with the neurodegenerative disease of frontotemporal dementia (FTD). We will apply two techniques known as knock-down, which direct complementary RNA to the site of a specific mutation as a tool to block the altered protein. The other approach is to cut DNA at specific regions of tau protein, thus downregulating expression of tau protein, for the purpose of curing familial FTD. Since abnormal tau aggregation is associated with AD, as well as a number of other diseases, these tau reduction techniques conceivably could also benefit those disease populations.
Using a mouse model, we are developing a way to reduce the expression of the tau protein, which is associated with FTD and aggregates in Alzheimer's disease (AD). We are using genetically modified mice that express the human tau gene with a mutation associated with FTD. We believe that some cases of FTD could be treated if the tau protein could be reduced. In our mouse model, we are applying two techniques known as tau knock-down, where complementary RNA is directed to specific sites of the mutation as a tool to block the altered protein. The other approach will cut DNA at specific regions of tau protein for the purpose of expressing less tau. Once we establish the tool to knockdown tau, we can then use it to assess how the features of both FTD and AD, as observed in the mouse model, are reduced or prevented after tau knockdown.
There are two unique aspects to this research. First, we use a newly-developed mouse model that utilizes reporters that are bioluminescent (glowing) to allow us to visualize tau expression in vivo. This model allows us to monitor tau levels over long periods and make real-time adjustments to the therapy. Second, we use “state-of-art” tau knockdown techniques. These techniques are complementary and reflect the latest technology tools for gene silencing (knockdown). Importantly, using the bioluminescence approach to monitoring tau expression allows us to directly screen our therapies in vivo, saving time and giving us much better prediction of efficacy in a living organisms. If successful, tau knockdown could be used in humans in several ways. The most obvious one would be in individuals that are at risk for FTD because they carry a mutant form of tau. Since abnormal tau aggregation is associated with AD, as well as a number of other diseases, reduction of tau may also be beneficial for those individuals.
About the Researcher
My career in the field of blood disorders began when I was a graduate student at University of North Carolina, Chapel Hill. I relocated to Mayo Clinic, Jacksonville, and joined the lab of Mike Hutton, PhD, essentially on the day that he and other researchers discovered the mutations in the tau gene that are associated with frontotemporal dementia. Utilizing the newly identified tau mutations, I created a genetically modified mouse model that developed some of the key pathological features of frontotemporal dementia and AD. After completing my post-doctoral position with the Hutton lab, I earned an independent position and was promoted through the ranks at Mayo Clinic where I continued my focus on mouse modeling of neurodegenerative diseases. In 2010, I moved to the University of Florida as an initial recruit to the newly-formed Center for Translational Research in Neurodegenerative Disease. The collaborative environment within our Center is incredibly supportive and beneficial for my research. I continue to develop mouse models for various neurodegenerative diseases, utilizing these models to explore the connection between these disorders and the development of potential therapies.
"I have always been drawn to puzzles and mysteries. Perhaps I was inspired by all of the Encyclopedia Brown books that I read as a child. There is nothing more enjoyable than taking clues that are seemingly unrelated, laying them out in my mind and establishing the relationship between the clues in order to solve a mystery. It is this mindset that drives my professional desire to go to work every day.
My research is not only a professional passion though. I am also driven by my personal connection to brain disorders. Initially, I was utilizing the opportunity at Mayo Clinic Jacksonville to build research skills that I hoped to eventually apply to psychiatric diseases. Soon after joining Mike Hutton's lab, several close family members developed AD, progressive supranuclear palsy, and related brain disorders. It was then that I decided I would dedicate my career to studying neurodegenerative diseases of aging.
I strongly believe that it requires collaborative spirit and teamwork to help us understand how AD and the related diseases develop and progress. Ultimately, this knowledge provides the foundation for developing therapies against these devastating diseases. I am so grateful that the BrightFocus donors have joined forces with our team of students, staff, and fellows to develop new therapeutic strategies against tauopathies. One thing that makes BrightFocus unique in its ability to stimulate AD research is the speed at which decisions are made and money becomes available. Some funding agencies have many research priorities and are very large, requiring multiple layers of approval for funding - oftentimes it may take 18 months to go from initially submission to receipt of funding. BrightFocus understands that individuals affected by tauopathies need therapies now."
First published on: July 10, 2015
Last modified on: July 1, 2018