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Northwestern University Feinberg School of Medicine

Faculty Profile: Tsutomu Kume, PhD Associate Professor of Cardiology and Molecular Pharmacology and Biological Chemistry

Tsutomu Kume, PhD

Cardiovascular development is at the center of all the work that goes on in Tsutomu Kume’s lab.

The cardiovascular system is the first functional unit to form during embryonic development and is essential for the growth and nurturing of other developing organs. Failure to form the cardiovascular system often leads to embryonic lethality, and inherited disorders of the cardiovascular system are quite common in humans. The causes and underlying developmental mechanisms of these disorders, however, are poorly understood. Kume works to better understand this development process using mice as animal models, as well as embryonic stem (ES) cells as an in vitro differentiation system.

Kume received a bachelor’s and master’s degree in science, and doctorate degree in molecular biology from the University of Tokyo, Japan. He completed his postdoctoral training in developmental biology at the Howard Hughes Medical Institute (HHMI) at Vanderbilt University Medical Center in 2000. After serving on the faculty of Vanderbilt University, Kume joined Northwestern University Feinberg School of Medicine in 2009.

What are your research interests?
As a postdoc more than a decade ago, I discovered that the Foxc1 and Foxc2 transcription factors are important for cardiovascular development. Specifically, my research group is seeking to explain the molecular basis for the role of Foxc1 and Foxc2 in the specification and differentiation of cardiovascular progenitors. In addition, my research has increasingly focused on understanding angiogenesis, the formation of new blood vessels from preexisting vessels, which is essential not only for embryonic development, but also for maintenance of adult tissues. This process is tightly regulated by the balance of pro- and anti-angiogenic factors, and many of these molecules are involved in both embryonic and pathological angiogenesis.

What is the ultimate goal of your research?
As a trained basic scientist, I am always aware of the impact of basic science research on clinical practice and how it can lead to new therapeutic applications for the treatment of disease. In that sense, I am delighted to be at Feinberg. I hope that my work in understanding the mechanisms of embryonic development will ultimately address a fundamental question, since many important molecules involved in embryonic development are postnatally “reused” in health and disease: How do tissues such as blood vessels normally form and go awry in the development of many diseases?

The ultimate goal of my research is to provide new insights into the mechanisms that lead to the development of therapeutic strategies designed to treat clinically relevant conditions of pathological neovascularization under ischemia, a restriction in blood supply, which includes myocardial infarction, known as a heart attack.

How does your research advance medical science and knowledge?
In collaboration with Dr. Ordan Lehmann, MD, PhD, associate professor, Departments of Ophthalmology and Medical Genetics, University of Alberta in Canada, our research team has recently identified Foxc1 as a master regulator in inhibiting the formation of blood vessels, and thereby maintaining clarity of the cornea of the eye in humans and mice.

Our new finding, published in the Proceedings of the National Academy of Sciences USA (PNAS), is clinically important because Foxc1 could possibly be used as gene therapy to treat diseases that cause blindness. One possible use might be in corneal transplants, where the growth of new blood vessels onto the transplanted cornea is a major problem. Our new approach may also be applicable to the treatment of other vascular-related disorders such as cancer. I gave a talk about this project at the Gordon Research Conference in March.

What types of collaborations are you engaged in?
During the past two-and-a-half years since my lab relocated to Northwestern, through collaborations, we have expanded our work into clinically related research. In particular, the Feinberg Cardiovascular Research Institute has been performing cutting edge research, and it was especially appealing for me to join such an extraordinary group. We have also been collaborating with Samuel Stupp, PhD, director atInstitute for BioNanotechnology in Medicine, Thomas Meade, PhD, professor of radiology, and Harris Perlman, PhD, associate professor of medicine-rheumatology, for our newly funded NIH-sponsored program project grant aimed at advancing the therapeutic use of endothelial progenitor cells for the treatment of cardiovascular diseases.

As another ongoing collaboration, Lehmann and I are planning to submit a new grant to test if exogenous Foxc1 inhibits the formation of blood vessels in the injured cornea in mice by using different approaches of gene delivery.

I am also part of the organizing committee composed of researchers from Northwestern and the University of Chicago for the 2012 Weinstein Cardiovascular Development Conference, which will be held in Chicago in May 2012.

How did you become interested in this area of research?
In the end, it was all about connecting the dots. My research interests have evolved over the years. As a graduate student working on a project of leukemia cells in Japan, I became interested in developmental biology by reading the literature. It was at the time when knockout mouse technology using ES cells was newly developed, and developmental biologists were the pioneers to employ this top-notch technique.

In 1996 I joined the laboratory of Brigid Hogan, PhD, an HHMI investigator at Vanderbilt University at that time and now chair of the Department of Cell Biology at Duke University. After publishing a couple of papers from her lab, I borrowed a protocol from another lab and did whole mount CD31 immunostaining of early wild-type embryos to see blood vessels. It worked very well, and I was very fascinated with the well-coordinated formation of blood vessels in the developing embryo. I found it beautiful and wanted to know how blood vessels can develop the entire vasculature, so that’s why I decided to move to cardiovascular research. It was not easy at the beginning because no one was working on this area of research in the Hogan lab, but it has turned out to be one of the best decisions of my life.

The start of the recent cornea project was also intuitive. From my postdoctoral work and that of others in 1999, it had been known that Foxc1 is critical for the development of the eye, and that mutations of human Foxc1 cause congenital glaucoma. But when my lab newly generated conditional Foxc1 knockout mice for other reasons a couple of years ago, I thought I might have missed something important in the eye. We revisited it and surprisingly found abnormal growth of blood vessels in the mutant corneas. Vascular development became my favorite and strongest area of research.

Who inspires you?
I have benefited from good mentors, including my doctorate and postdoctoral mentors, Michio Oishi, PhD, and Brigid Hogan, PhD, respectively, who have guided and nourished me to become a better scientist. They taught me how to tackle key biological questions, design research projects, and run my own lab. I have invited Brigid to host her Lectures in Life Sciences seminar here at Northwestern in May 2012. I’m very excited about it.