Jet setting isn’t usually synonymous with biomedical research, but in the case of University of Vermont Distinguished Professor and Chair of Pharmacology Mark Nelson, Ph.D., it’s a routine that ensures scientific progress. Since receiving a Fondation Leducq Transatlantic Networks of Excellence grant with collaborator Anne Joutel, M.D., Ph.D., at the University of Paris in October 2012, he has traveled to Europe a half a dozen times. His – and the Network’s – objective is to conduct intensely focused, fast-moving, and highly productive scientific research to identify the genes driving a rare genetic disorder involving the brain’s small blood vessels called CADASIL – an acronym for Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy.
In reality, explains Nelson, the number of people suffering from the disorder, which causes multiple small strokes and leads to cognitive impairment and dementia, is relatively small (about one in 50,000 people are affected). However, non-genetic causes of small vessel disease (SVD) account for about 25 to 30 percent of ischemic strokes and are a leading cause of cognitive decline and disability. In studying small vessel physiology and pathophysiology in CADASIL– specifically the molecular mechanisms responsible for local control of blood flow in the brain – the team’s work will provide a window into the common denominators shared by all blood vessel problems in the brain, including hemorrhagic stroke, and the more common SVD.
Nelson and Joutel’s Network of Excellence, titled “Pathogenesis of Small Vessel Disease of the Brain,” was selected from 96 grant submissions as one of four networks to receive Fondation Leducq funding in 2012. As North American and European coordinators respectively, Nelson and Joutel held the Network’s first meeting in Munich, Germany, this past March, and will gather their group again in September in Paris. A U.S. meeting – location still to be determined – will be held in spring 2014. This past June, Nelson flew to Erfurt, Germany to present the keynote Ferid Murad Lecture at the Sixth International Conference on cGMP – short for cyclic guanosine monophosphate, an enzyme that regulates metabolic processes – which focuses on research in the field of cGMP generators and effectors, as well as their pathophysiological and pharmacological implications.
Nelson isn't alone in his journeying; travel to ensure ongoing research collaboration is a critical part of the grant, and network members from both sides of the Atlantic have had the opportunity to work with senior investigators at the U.S. and European sites. In fact, a steady stream of graduate students and post-doctoral fellows have made the trip from European countries, including Denmark, France, Germany, Spain, and the United Kingdom, as well as India, to work in Nelson’s lab. Post-doctoral fellow Fabrice Dabertrand, Ph.D., is a primary Leducq project investigator, and regularly treks between Nelson’s and Joutel’s labs. Christel Krøigaard, Ph.D., a postdoctoral fellow at UVM with support from the Lundbeck Foundation, has recently joined the network. Network administrator and pharmacology staffer Allison Sturtevant manages the details of these comings and goings, as well as keeps all the elements of record-keeping and finances for the grant in order.
At the heart of the Network’s research program, which got underway in January 2013, is a mouse model of CADASIL developed by Joutel, which has a mutation in the Notch3 gene proven to play a role in CADASIL. “It’s only found in smooth muscle cells in the brain,” explains Nelson, who adds that Joutel's model possesses “most of the salient pre-clinical features of the human disease.”
These mice, explains Nelson, develop deposits – called granular osmiophilic material deposits or GOM for short – around the blood vessels in the brain similar to those found in Alzheimer’s disease patients, so are a rich source of genetic information. Isolating the brain’s small blood vessels, shares Nelson, is a challenging process; each vessel measures about 20 microns in diameter. “We overcame that with the mouse model,” he says.
In addition to studies of this model, Nelson’s European collaborators are collecting and conducting biochemistry analyses of post-mortem samples from CADASIL patients.
“People with this mutation typically experience migraine with aura in their 20s and then progress to dementia in their 30s and 40s due to series of small strokes,” says Nelson. “They don’t usually live past 60.”
The group aims to determine the commonalities among patients with CADASIL and those with non-genetic small vessel disease. One approach – using fMRI scanning – will provide the researchers with a visual comparison of the vessels of CADASIL patients and non-genetic disease patients.
The genetic disorder is found in all of the patient’s small blood vessels, but, wonders Nelson and colleagues, why are the vessels in the brain versus the kidney, for example, affected? “We want to know what it is about those vessels that make them susceptible,” Nelson says. Determining exactly when and how the first symptoms occur by looking at the early stages of this progressive disease, is one of the Network’s main objectives.
The Leducq grant complements both Nelson’s $12 million, five-year National Institutes of Health (NIH) Program Project Grant on local control of blood flow in the brain and in stroke, as well as his Totman Medical Research Trust work, which has a cerebrovascular focus. Among the UVM faculty members involved in these two grants, as well as the Leducq grant, are Professors of Pharmacology Joseph Brayden, Ph.D., and George Wellman, Ph.D., as well as Professor of Neurology Marilyn Cipolla, Ph.D.
None of the group’s work – or the grant – would have been possible without the important and longstanding research collaboration between Nelson and Joutel. Nelson’s two other critical U.S. partners – Michael Kotlikoff, V.M.D., Ph.D., dean of the College of Veterinary Medicine at Cornell University, and Luis Fernando Santana, Ph.D., professor of physiology and biophysics at the University of Washington, both with whom he collaborates on his Program Project Grant – are key to ensuring the Leducq grant’s success.
“Funding from organizations like Leducq and Totman has enabled us to do things and have interactions within the University that wouldn’t have been possible with conventional grants,” admits Nelson, who adds that the work supported by these funds, as well as his NIH Program Project Grant, “make us one of the best places in the world for brain blood vessel research.”