A professor at Washington University in St. Louis, Missouri, has been awarded two grants from the National Institutes of Health (NIH) totaling over $4.5 million to study Huntington’s disease (HD) and the causes behind this devastating disease.
The recipient of the grants is Rohit V. Pappu, the Edwin H. Murty Professor of Engineering at Washington University, who lectures at the School of Engineering & Applied Science.
With one grant of $2.84 million, Pappu and his research partners, Marc I. Diamond, M.D., of the University of Texas Southwestern Medical Center, and Ralf Langen of theUniversity of Southern California, will study how to mimic profilin – the protein that modulates the clumping of the huntingtin gene. Profilin is known to stick to three types of molecules, including stretches of the amino acid called proline.
“We are hoping that we can make profilin a better profilin,” Pappu said in a news release. “We can use it for mimicry purposes and also as an entity that gives us rules that we can adapt to other proteins that might interact with other aggregation-prone molecules that are implicated in diseases other than Huntington’s, such as Parkinson’s disease and Alzheimer’s disease.
“The idea is that over our aging process, the regulation or dysregulation of modulatory proteins within cells might be the loss of one of our lines of defense against neurodegeneration that is associated with the clumping of proteins such as huntingtin,” Pappu added.
The additional five-year extension grant of $1.67 million was given to the research team to study how the mutations within the repetitive region of huntingtin, and its flanking sequences, modulate the stickiness of the protein.
“We are also building toward taking those findings and heading in the direction of asking what sort of cellular processes are impaired because huntingtin is sticking to itself,” Pappu said. “That will be the key question necessary to answer to figure out why the stickiness leads to neuronal death. Until we have something that approaches a persuasive answer to that question, finding a cure becomes a tricky proposition.”
“One grant looks at huntingtin from the vantage point of the other molecules in the cell, and the renewal grant is looking at the cellular milieu from the huntingtin side,” Pappu explained. “The goal is that you have to look at the same molecule from all sides, and this is what we are doing with huntingtin. The central tenet here is that if you know how something works, you can mimic it — it’s a sound engineering principle.”
Pappu and his team started working in 2010, when they received a grant from the Hope Center for Neurological Disorders at the School of Medicine, where Diamond was a professor of neurological disorders at the time, and still serves as an adjunct professor. That grant for the pilot program provided the space they needed to start asking challenging questions about Huntington’s disease.
“These pilot programs are an important feature of the research ecosystem at Washington University, and they highlight one of the major strengths of this institution — that there are no barriers between the School of Medicine and Engineering,” Pappu said. “They highlight what centers can do in our ecosystems if they have resources.”