Searching for drugs that affect migrating cells
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Zebrafish movie showing fluorescently labeled immune cells migrating from the bloodstream (top) to the site of a wound (bottom).
Though cell movement and migration in the body play a central role in mediating injury and disease, including inflammatory responses and cancer metastasis, drugs designed to stifle cells’ nomadic tendencies are scarce.
Through the Discovery Seed Grant Program, a research team seeks to develop a novel drug discovery process that may start to fill this gap. Using a two-tiered approach, the nine-member team will sort through libraries of chemical compounds and search for agents with promising anti-migration properties.
“Our approach is to develop tools useful for identifying drugs that will target cell migration,” explains lead investigator Anna Huttenlocher, a professor of pediatrics and pharmacology. “These types of drugs will be useful for applications in cancer and inflammatory disease.”
Tiny channels
The researchers will first screen compounds in an engineered microfluidics device. Cells placed in a tiny channel can migrate or remain stationary in response to different chemical cues, such as the signals that draw immune cells to inflamed tissues and those that tell the cells to linger once they arrive.
Solutions of test compounds can be added and analyzed for the ability to affect the cell migration. Automating the procedure with robots and computers should allow rapid testing of large numbers of compounds, a critical feature of any drug discovery process.
The Team
Principal Investigator
- Anna Huttenlocher, Pediatrics, Pharmacology
Investigators
- David Beebe, Biomedical Engineering
- Mary Halloran, Zoology
- Richard Hutchinson, Pharmacy, Centrose, LLC
- Robert Jeraj, Medical Physics
- Fong-mei Lu, Visiting Scholar
- Kristyn Masters, Biomedical Engineering
- Michael Merline, West High School, Madison, WI
- Ben Shen, Pharmacy
- James Stewart, Curriculum and Instruction
“The application of cell migration screens to drug discovery platforms has not been made because of the difficulty of these types of assays. We propose to develop assays that are easy to use and therefore feasible for larger-scale screening of chemical libraries,” Huttenlocher says. “This type of approach has great potential for identifying novel drug targets.”
Fishing further for promising drugs
Promising compounds will be further tested for their ability to affect cell migration and inflammation in the context of a whole animal – in this case, zebrafish. Strains of the small aquarium fish genetically engineered to have fluorescently tagged immune cells will allow the researchers to observe the effects of potential drugs on cell migration in real time.
They hope to identify new compounds with therapeutic potential, says Huttenlocher. “Our end goal is to have a real clinical application.”
An additional component of the project will adapt the drug-screening model to be used as an educational tool for high school and college students to teach methods of biology, experimentation and drug discovery.
The project’s other investigators are David Beebe and Kristyn Masters, biomedical engineering; Mary Halloran, zoology; Richard Hutchinson, pharmacy and Centrose, LLC; Robert Jeraj, medical physics; Fong-mei Lu, a visiting scholar; Michael Merline, a teacher at West High School in Madison; Ben Shen, pharmacy; and James Stewart, curriculum and instruction.