Michelle Ozbun, PhD, enjoys the process of scientific discovery. “We have no idea what we’re going to find out,” she says. Ozbun is referring to the two grants she was awarded to study human papillomavirus infection and cell signaling. Her two-year, $960,000 grant from Johnson & Johnson will focus on the process HPV uses to infect cells. Her five-year, $1.7 million grant from the National Institutes of Health will focus on epithelial growth factor receptor and how it tells the cell to take in a virus.
The grants focus on basic science discoveries, but Ozbun and her team also hope to develop new ways in which to measure infections. The basic science and new measurement methods could be used in many ways. Johnson & Johnson is particularly interested in better ways to sterilize medical devices. Others could be interested in developing new ways to treat people who are already infected with HPV. “It’s hard to predict,” says Ozbun of her research. “That’s the cool part about it.”
Ozbun, at The University of New Mexico Comprehensive Cancer Center, is among a handful of international experts who study HPV and its effect on cells and people. HPV, like all viruses, cannot reproduce on its own. A virus particle must get inside a cell and use the cell’s equipment to make more virus particles.
Endocytosis is the process cells use to take in nutrients and other molecules from their surroundings. Ozbun thinks HPV might use this process to sneak inside. “Nobody knows what receptor or receptors the virus binds to that tell the cell to start the endocytosis process,” says Ozbun. But she and her research team have a strong guess.
Ozbun and her team have shown that HPV virus particles bind to molecules in the extracellular matrix and on the surface of skin cells. The extracellular matrix is the scaffolding around cells. It protects them and gives the tissue its structure. Blood has a liquid extracellular matrix and bone has a hard extracellular matrix. Cells produce the molecules that form the extracellular matrix surrounding them.
The extracellular matrix also holds important growth factors. Growth factors are molecules that stimulate cells to grow. In skin, for example, growth factors help cells to heal a wound.
Some molecules in extracellular matrix are electrically charged. HPV virus particles are also electrically charged. Ozbun thinks HPV virus particles can bind to the electrically-charged molecules in the extracellular matrix and on the surface of the cells. But, to cause an infection, the virus still needs to get inside a skin cell.
Ozbun explains that cells get chemical signals from the extracellular matrix constantly. The signal molecules attach to receptors on the cell surface. A receptor changes shape when the specific molecule for which it was built attaches to it. This shape change touches off the cascade of chemical changes within the cell that the signal molecule was meant to induce. Sometimes, those chemical changes cause the cell to take in the receptor and whatever is attached to it.
Ozbun thinks HPV hijacks this process. She suggests a theory in which HPV virus particles attach to electrically-charged extracellular matrix molecules that also hold growth factors or signal molecules. When these molecules attach to epithelial growth factor receptors, or EGFRs, on a cell’s surface the cell takes these molecules in. And, the cell takes the attached HPV virus particles in, too. “So the virus is just piggybacking on these normal processes,” says Ozbun. “It’s like a Trojan Horse. It would be really hard to help the cell differentiate [the HPV virus particle].”
To test this theory, the Ozbun team is creating new measurement methods. One method they’re developing will help them to see cells that are producing HPV RNA. RNA, or ribonucleic acid, carries instructions for making proteins to the structures in the cell that make them. So cells infected with HPV would have RNA that encodes for HPV proteins.
Ozbun and her team can use special microscopes at UNM to see HPV RNA. “It works as proof-of-concept right now,” she says. They hope to program software that will measure how many cells are infected and how much HPV RNA each cell has.
In another method, the team is perfecting a technique to capture the moment when the cell takes in the HPV virus particle. They want to know what else the cells takes in when it takes in HPV. Knowing that, they think, will help them learn more about the cellular changes EGFR induces and that HPV uses to trick its way in.
Ozbun is working with physicians and other scientists at the UNM Comprehensive Cancer Center to collect skin and other samples from people infected with HPV. Using samples from people will allow the Ozbun team to compare how HPV grown in a lab may behave differently from HPV that passes between people. And, Ozbun hopes that learning the fundamentals of the infection process will lead to treatments, new ways to prevent infections, and uses she can’t even imagine yet.
Michelle Ozbun, PhD, holds Professorships in the Department of Obstetrics & Gynecology and in the Department of Molecular Genetics & Microbiology at The University of New Mexico School of Medicine. She is The Maralyn S. Budke Endowed Professor in Viral Oncology. Dr. Ozbun is a full member of the Translational Cancer Biology and Signaling Research Group at the UNM Comprehensive Cancer Center and is co-leader of the Head and Neck Cancer Clinical Working Group.
The National Cancer Institute of the National Institutes of Health supported the research reported in this publication under Award Number CA207368, Principal Investigator: Michelle A. Ozbun. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
The University of New Mexico Comprehensive Cancer Center is the Official Cancer Center of New Mexico and the only National Cancer Institute-designated Cancer Center in a 500-mile radius. Its 125 board-certified oncology specialty physicians include cancer surgeons in every specialty (abdominal, thoracic, bone and soft tissue, neurosurgery, genitourinary, gynecology, and head and neck cancers), adult and pediatric hematologists/medical oncologists, gynecologic oncologists, and radiation oncologists. They, along with more than 600 other cancer healthcare professionals (nurses, pharmacists, nutritionists, navigators, psychologists and social workers), provided cancer care for nearly 60 percent of the adults and 70 percent of the children in New Mexico affected by cancer. They treated 11,928 patients in 92,551 ambulatory clinic visits in addition to in-patient hospitalizations at UNM Hospital. These patients came from every county in the State. More than 12 percent of these patients participated in cancer clinical trials testing new cancer treatments and 35 percent of patients participated in other clinical research studies, including tests of novel cancer prevention strategies and cancer genome sequencing. The 130 cancer research scientists affiliated with the UNMCCC were awarded almost $50 million in federal and private grants and contracts for cancer research projects and published 301 high quality publications. Promoting economic development, they filed more than 30 new patents in FY16, and since 2010, have launched 11 new biotechnology start-up companies. Scientists associated with the UNMCCC Cancer Control & Disparities have conducted more than 60 statewide community-based cancer education, prevention, screening, and behavioral intervention studies involving more than 10,000 New Mexicans. Finally, the physicians, scientists and staff have provided education and training experiences to more than 230 high school, undergraduate, graduate, and postdoctoral fellowship students in cancer research and cancer health care delivery. Learn more at cancer.unm.edu.
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