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Northwestern University Feinberg School of Medicine
Research

Faculty Profile: William A. Muller, MD, PhD

William A. Muller, MD, PhD

What are your research interests?
We study the cellular and molecular basis of inflammation, which is at the root of most human disease. In particular we study the regulation of diapedesis—the step in inflammation in which white blood cells (leukocytes) squeeze between the endothelial cells that line the blood vessels at the site of inflammation. This is the “point of no return” of the inflammatory response, so in addition to being a fascinating basic science problem involving intra- and intercellular signaling, it is a prime target for therapeutic intervention.

My lab has identified and characterized a number of molecules on leukocytes and endothelial cells that are critical for diapedesis and hence, for inflammation. Platelet/endothelial cell adhesion molecule (PECAM or CD31) is the best characterized of these. Interaction between PECAM on the leukocyte and PECAM on the endothelial cell triggers signals in both cells that are required to initiate diapedesis. If we inhibit PECAM function on either cell, we selectively block the ability of leukocytes to enter the junction and block inflammation in a number of animal models of inflammatory diseases. CD99, also expressed on both leukocytes and endothelial cells, plays a critical role in a later stage of diapedesis. If we block CD99 on either the cell, the leukocytes enter the junctions, but get stuck partway through. PECAM and CD99 thus define two molecularly dissectable steps in diapedesis.

In studying diapedesis, we have discovered a novel organelle in endothelial cells, the lateral border recycling compartment (LBRC). This reticulum of membrane vesicles remains just below the plasma membrane surface along the borders between endothelial cells. Membrane recycles between this compartment and the cell junctions; however, when a leukocyte begins to migrate across the junction, recycling is rapidly redirected to the site of diapedesis. The compartment contributes a large amount of membrane surface area as well as PECAM and CD99 molecules to aid the passage of the leukocyte. This “targeted recycling” of membrane from the LBRC is absolutely required for diapedesis. Even more exciting are data showing that the mechanisms controlling the formation and trafficking of LBRC membrane are different from those of other recycling membrane compartments in the cells. This provides potential opportunities to interfere with movement of this compartment and block inflammation without disrupting normal membrane trafficking necessary for cell survival.

Why study the cellular and molecular basis of inflammation?
Almost all disease is due to uncontrolled or misdirected inflammation We think of maladies such as rheumatoid arthritis and asthma as being inflammatory diseases. However, atherosclerosis, which leads to heart attacks and strokes, is an inflammatory disease of arteries. In fact, much of the natural history of cancer involves interactions of the tumor cells with the host’s inflammatory and immune responses. If we understand how to regulate inflammation, we could potentially enhance it where we need to—for example in people who are immunodeficient due to HIV, leukemia, or chemotherapy—and block it where the inflammatory response is causing damage.

What are some of your current research projects?
We are attempting to purify membrane of the LBRC by cell fractionation. This will provide the opportunity to identify all of its protein and lipid components and have a better idea of how its formation and motion are regulated.

We are examining the signaling pathways generated in both leukocytes and endothelial cells by interactions of PECAM and CD99 in an attempt to understand better the role these molecules play in diapedesis. We are testing all of the observations that we make in vitro using mouse models of dermatitis, peritonitis, rheumatoid arthritis, multiple sclerosis, pulmonary fibrosis, and atherosclerosis. We use transgenic and “knockout” technologies for these experiments as well as interference using monoclonal antibodies to mouse PECAM and CD99. We are starting work using intravital microscopy to examine the events of diapedesis in living animals in real time.

Why did you choose FSM?
Northwestern has a strong collaborative academic environment. The support of NMH for our academic mission will provide resources that will allow basic and translational research to really take off. I want to recruit a critical mass of people performing cutting-edge research in inflammation. Since inflammation is at the root of most diseases, this group will be able to form great collaborations not only with other investigators already at NU studying inflammation, but also with scientists in virtually every department. There is a tremendous opportunity for basic and translational research.

What is the biggest challenge you have experienced so far?
The biggest challenge I’ve experienced is stepping into the position of Chairman in a clinical department. I got to this position because of my accomplishments in research and academic medicine. I never took a course in economics. Now I have administrative and financial responsibilities that require whole new skill sets and knowledge that they didn’t teach in medical school or graduate school. It is really a challenge trying to learn these skills “on the job.”

What does the future hold for the Dept. of Pathology?
I sincerely hope that the Pathology Department will take the lead in catalyzing translational research. We are in the process of revitalizing the Pathology Core Facility. Our goal is to make it a state-of-the-art research facility and reference laboratory for the entire medical center. I want our research recruits to form a highly collaborative group that will help FSM become the research Mecca that we would all like it to be.

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