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Three UNC Lineberger researchers are collaborating on a project recently awarded more than $3.3 million over five years from the National Institutes of Health’s National Heart, Lung, and Blood Institute.

Claire Doerschuk, MD, Keith Burridge, PhD and Klaus Hahn, PhD are co-PIs of this multi-PI award to investigate pulmonary inflammation at the cellular level.

“This is an important mechanism to understand because pulmonary diseases associated with the greatest risk for lung cancer are characterized by inflammation,” says Doerschuk, who is also professor of medicine and pathology, director of UNC’s Center for Airways Disease and a member of UNC’s CF/Pulmonary Research & Treatment Center.

Inflammation is characterized by the migration of neutrophils – white blood cells that are the vanguard of the immune system – to the site of inflammation. Using a technique developed at UNC by co-investigator Klaus Hahn, PhD, Thurman Professor of Pharmacology, the team will use light to manipulate the activity of key proteins related to neutrophil movement at precise times and places within a living cell.

The team will also look at the activity of a class of proteins called RhoGEFs, factors that activate Rho proteins which are part of the RAS superfamily – a class of proteins associated with cancer activity. Keith Burridge, PhD, Kenan distinguished professor of cell and developmental biology, is an expert in Rho proteins and their regulation. The group will also test unique technology developed at UNC by Richard Superfine, PhD, Taylor-Williams Distinguished Professor of Physics and Astronomy. The experiments will use three dimensional force microscopy to mimic the tension on cells that occurs during neutrophil adhesion and migration in the lung. In a previous study supported by a UCRF award from the LCCC, Burridge and Superfine collaborated showing that the force microscopy technique offers Rho protein activation in cells responding to mechanical tension.

Superfine’s technique applies magnetic particles to cells and then uses magnets to exert force on the cells – creating extracellular tension. Burridge’s and Doerschuk’s teams, in turn, can measure the effect of this force on key proteins that control neutrophil movement in lung tissue and form the basic mechanism behind inflammatory disease.

“This grant is a stellar example of how outstanding scientists at UNC from different classical disciplines apply completely new approaches to important clinical questions. Understanding the fundamentals of lung inflammation will give us clues as to how to prevent or detect lung cancer earlier,” said H. Shelton Earp, MD, director of UNC Lineberger.

“The collaborative environment, brilliant faculty and novel technology at UNC make this possible,” he added.

Photo caption: Neutrophil adherence induces an increase in the phosphorylated p38 MAPK in TNF–a–pretreated pulmonary microvascular endothelial cells. The distribution of phosphorylated p38 (green) and F-actin (red) in ECs without neutrophils or with neutrophils adherent for 2 or 6 min was examined using confocal microscopy. A representative image through a slice of ECs is shown, and the arrows indicate the position of adherent neutrophils. Quantification of many images revealed that the number of pixels showing bright staining for phosphorylated p38 MAPK increased in endothelial cells at 2 and 6 minutes of neutrophil adherence. Wang Q et al., AJP Lung Cell Mol Biol 288:L359-369, 2005.