March 2005, Issue 4

Tufts-NEMC MCRI Begins Broad Collaborative Studies on Blood Vessel Function

The Molecular Cardiology Research Institute at Tufts-NEMC has received an $11.3 million, five-year renewable program project grant from the National Heart, Lung and Blood Institute. A broad coalition of researchers from Tufts-NEMC and other research institutions will be exploring vascular health and disease in a multi-tiered approach. An integrated suite of projects will examine a new hypothesis about the causes of hypertension, and the work will range from studies of people living in the community to studies of proteins and molecules that regulate how blood vessels contract and relax.

“The dogma is that the main causes of hypertension in people have to do with abnormalities in the kidney rather than the blood vessel, and that these kidney abnormalities lead to excessive salt and water reabsorption that expands blood volume,” says Howard Surks, a Tufts-NEMC MCRI investigator. The program project is testing an alternative hypothesis, namely that the causes of hypertension lie in the blood vessels themselves. From population-based to cell-based experiments, the interdisciplinary group will examine the genetics and the molecular mechanisms that govern the contractile state (or tone) of smooth muscle cells in blood vessels.

“The general hypothesis for the program, that primary abnormalities in vascular smooth muscle cells can be causal for the disease hypertension, is quite exciting to me,” says Michael Mendelsohn, Tufts-NEMC principal investigator and director of the program project grant. “If you take a hundred people who have high blood pressure, we only know the cause of the high blood pressure in between two and five of them. The cause for hypertension in the remaining 95 to 98 people is a big question mark. If even a small percentage of blood pressure abnormalities in humans are due to vascular smooth muscle cell abnormalities, it would be useful to know, because that’s many people, and because it directs us to a different diagnostic and therapeutic approach.”

Proteins that regulate vascular smooth muscle cell (VSMC) contraction are the specific focus of the project. These include three proteins known to be essential for normal blood pressure − RGS2, the regulator of Gq-protein signaling; estrogen receptor (ER)β; and the calcium-activated potassium channel (BKCa) − as well as the two most physiologically relevant myosin phosphatase regulatory kinases, cyclic GMP-dependent protein kinase (PKGIα ), which promotes vascular relaxation, and Rho kinase (ROCK), which inhibits vascular relaxation.

The grant funds four projects and two core facilities. Project 1 is entitled “Genetics of Vasorelaxation and Cardiovascular Responses” and is directed by David Housman of Massachusetts Institute of Technology. Major portions of Project 1 are being done at Tufts-NEMC under the direction of Gordon Huggins. Statistical work is being done by Inga Peter and Chris Schmid in the Tufts-NEMC Institute for Clinical Research and Health Policy Studies. The Housman genomics laboratory will receive samples from several population-based longitudinal studies, including the Framingham Heart Study, which has been collecting health information from thousands of people since 1971 and blood samples for DNA extraction since 1986. Project 1 will correlate blood pressure data with genetic information obtained from blood samples from several generations of families. It will look at four particular genes in depth: two kinases (PKGIα and ROCK), the BKCa channel, and (ER)β. Daniel Levy, director of the Framingham Heart Study, will serve as the senior clinical scientist on the blood pressure association analyses.

Project 2 is entitled “Mechanisms of PKG-mediated Vascular Relaxation” and is directed by Michael Mendelsohn with Howard Surks as a co-investigator. Using molecular, cellular and in vivo physiological approaches, Project 2 will explore the biomolecular interactions among PKGIα and several VSMC proteins that affect blood vessel contraction and relaxation.

Project 3 is entitled “BKCa Channel Regulation by PKG in Vascular Smooth Muscle” and is directed by Daniel Cox of Tufts-NEMC and the Tufts University School of Medicine Department of Neuroscience. Collaborators include Mark Nelson of the University of Vermont and Richard Aldrich of Stanford University. Project 3 studies the activity of large-conductance, potassium-activated calcium channels, known as BKCa, and the mechanisms by which their regulation influences VSMC function.

Project 4 is entitled “Vascular Dysfunction as an Etiology of Hypertension” and is directed by Richard Karas of Tufts-NEMC. Collaborators include Tom Coffman of Duke University and Yan Zhu of Caritas St. Elizabeth's Medical Center. Project 4 will study blood vessel function and kidney function in both normotensive and hypertensive models in vivo. “Part of our idea for this whole program project grant is that we have projects going all the way from looking at genes [that cause high blood pressure in model systems] to looking for subtle alterations in those genes in people through the Framingham Heart Study,” says Karas.

Large program project grants such as this one have enormous advantages over smaller research projects and are becoming a preferred research format under the new NIH Roadmap. “One of the greatest advantages of a large program project grant is that you get additional funding for core facilities, which really facilitates collaborations among scientists,” says Karas.

Collaboration has benefits for both the infrastructure and the intellectual basis of research. “The variety of scientific approaches to the hypothesis being tested and the questions being asked are much greater when you put together a multi-investigator, multi-departmental and multi-institutional program,” says Mendelsohn. “So the range of approaches in our program project grant is from the very basic molecular cell biology of vascular smooth muscle all the way up to looking at associations between variants in smooth muscle cell genes and high blood pressure in humans. Also, the level of technological sophistication that you can bring to bear on a question is greater because you are able to pool resources.

“The more people you have thinking about a problem together and talking about it from different directions, the more likely you are to come up with creative approaches and interesting ways of testing the hypothesis. We’re all meeting regularly, talking about what’s coming, sharing data that are not published, being creative together, serving as sounding boards and constructive critics for each other. There’s an enormous energy and momentum this brings to the process. And it’s a lot more fun to do science this way. People have a good time. They meet a lot of new people. They think about things from a direction they’ve never thought about them from before. That’s a very big part of it for us all.”

For more information, go to http://www.nemc.org/mcri/

 

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