The vascular system represents an exquisite feat of bioengineering. Fluid (blood) flow and mass transfer are intimately integrated with and actively regulate vascular cell responses. Therefore, elucidating the molecular nature of cellular processes in the dynamic setting of the vasculature requires the synthesis of engineering principles with quantitative modeling and molecular cell biology.
My research in Molecular and Cellular Bioengineering is directed at developing a mechanistic understanding of the effects of shear stress due to fluid flow on gene regulation and receptor-mediated cell-cell interactions pertinent to cancer metastasis, thrombosis and inflammation/infection, three of the most critical pathological processes affecting mankind. The ultimate goal of my research program is to develop molecular-targeted therapies to combat these disorders, using a directed multi-disciplinary approach by integrating engineering fundamentals with biophysical models and concepts from biochemistry and molecular cell biology.
FEATURED ARTICLE: Offering a “Sweet” Clue to Blood Borne Cancers
The surfaces of all cells–both normal ones and cancer causing—are coated with tiny sugar molecules that bind to compatible sites on blood vessel walls and allow the cell to travel around the body and into tissues. But what starts out as a friendly molecular “handshake” for normal cells turns into a deadly embrace where tumor cells are involved.
Researchers from the Whiting School of Engineering and the School of Medicine at Johns Hopkins University are examining the sticky interaction between the sugars that coat tumor cells and three sugar binding proteins found on blood vessel walls called selectins. If they can block the interaction between selectins and the sugar molecules on the outer surface of cancer cells, they may find a new way to halt the spread of the disease.
“Selectins on the vessel walls are involved in normal physiological processes, so we need to preserve them,” says Konstantinos Konstantopoulos, professor and chair of the Department of Chemical and Biomolecular Engineering and faculty member of the Institute for NanoBioTechnology. “Instead, we are looking for ways to block the sugar-carrying molecules expressed on tumor cell surfaces.”
Collaborating with Ronald Schnaar, professor of pharmacology and neuroscience at the School of Medicine, Konstantopoulos identified which sugar-carrying molecules recognized which selectins. Then, the team used genetic interference to “knock down” the expression of these sugar-carrying molecules on the tumor cell’s surface. Using a technique called “cell rolling,” they flowed a mixture of tumor cells both with and without the sugar-carrying molecules past a surface where some compatible selectins had been fixed. Tumor cells expressing the sugar-carrying molecules slowed down and rolled along the surface near the selectin, while those without, flowed by without stopping.
“This rolling is the beginning of the molecular ‘handshake’ between the selectin and the sugar,” Schnaar says. “Rather than becoming immediately fixed, rolling allows the cell to sample its environment and determine if it is safe to proceed.” This work was published in the June 2008 issue of the Journal of Biological Chemistry. The Konstantopoulos’ Lab Web site features two short animations that visualize the rolling motion created by the interactions of the sugar molecule and selectins.
In another study with Kathleen Stebe, a research professor at Johns Hopkins and affiliated faculty member of INBT, Konstantopoulos uses nanotechnology to investigate how rapidly the interactions between the tumor cell sugar molecules and the vessel wall selectins occur. In addition, Ziqiu “Tommy” Tong, one of INBT’s NanoBio Medicine fellows, is examining the potential for these concepts to be used in a nanoscale biosensor for early-stage cancer cell detection.
Konstantopoulos imagines many other potential applications, such as nanobeads loaded with anticancer drugs that could target delivery and help avoid the typical adverse side effects of chemotherapy. For the time being, however, their work remains largely investigative. “A therapeutic application is two steps beyond where we are now,” adds Schnaar.
Open Postdoc Position
One position in the field of biophysics of receptor-ligand binding is available in the laboratory of Dr. Konstantopoulos). Candidates should have a Ph.D. in Bioengineering, Biophysics, Biochemistry or a related discipline with a strong record of publication and experience in the biophysical and biochemical characterization of glycoproteins.