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Spring 2010, Issue 11

Regenerative Properties of the Sonic Hedgehog Gene

Roberto Pola, MD, PhD, joined the Center for Cardiovascular Research at Caritas St. Elizabeth's Medical Center (CSEMC) in 2008 as an associate investigator. He is also an assistant professor in the Department of Medicine at Tufts University School of Medicine and has an adjunct position at the Center of Cancer Systems Biology at CSEMC. Pola’s research into angiogenesis (growth of new blood vessels) and myogenesis (growth of new muscle tissue) could lead to therapeutic treatments for diseases such as myocardial infarction and muscular dystrophy.

Pola received his MD and PhD (in molecular biology) from the Catholic University School of Medicine in Rome. He completed clinical training with a residency in geriatrics at the A. Gemelli University Hospital in Rome, where he also headed the Laboratory of Vascular Biology and Genetics. He then worked as a postdoctoral fellow at CSEMC in the laboratory of the late Jeffrey Isner and Douglas Losordo (see Research News Losordo article) and as a visiting assistant professor in the Department of Anatomy and Cellular Biology at Tufts University School of Medicine.

A central theme in Pola’s work over the past several years has been the sonic hedgehog gene. This unusual name was given by the scientist who discovered the gene, after the video game character “Sonic the Hedgehog.” The hedgehog gene is so named because in the fruit fly, where it was first discovered, a malfunctioning gene caused the larvae to be spiky, like the spines of a hedgehog. Other genes in the family are named after real hedgehogs—one is called Indian hedgehog, another desert hedgehog. Hedgehog genes have been known for years to be important for embryonic development; they have been recognized more recently as prime players in adult tissue repair.

“We have found that sonic hedgehog is an important angiogenic factor,” says Pola. “So we hope to use this molecule to treat diseases where there is reduced blood flow, like in myocardial infarction, peripheral artery ischemia, or ischemia of the heart.” A new direction for the lab is to move beyond angiogenesis to myogenesis, the regeneration of muscle tissue. “We found out that sonic hedgehog is able to regulate regeneration of adult muscle after injury,” says Pola. “This is very interesting because it could be important for diseases like muscular dystrophy.” Pola’s research group is looking at the sonic hedgehog gene in mouse models of both ischemia and muscular dystrophy. They clone the human gene in bacteria, incorporate it into a plasmid, and inject it into the target tissue. After 15 to 30 days, they compare tissue regeneration in mice that harbor or lack the sonic hedgehog gene. “With the treatment with sonic hedgehog, we want to see if we can stop the process of degeneration and stimulate the process of regeneration,” says Pola. “The next step will be to search for additional funding to move into more complex or larger animal models, or even to human trials.”

Another project of the Pola research group is to identify genes that increase the risk of cardiovascular disease. “If you identify a gene with a function that actually increases the risk over time to develop myocardial infarction or stroke, it would be important to identify the people at high risk in order to treat these people more aggressively,” says Pola. “We have identified a set of genes that, when considered together, predict with a very strong power the incidence of stroke in subjects affected by type 2 diabetes. This was done in collaboration with a group in Scotland who have been following a large cohort of people with type 2 diabetes.” At first Pola and his group looked at genes associated with inflammation, since inflammation is involved in the development of atheroslerosis and ischemic diseases. “Some of these genes had been associated with stroke in the literature,” says Pola. “Some were instead identified by us through educated guesses initially, then refined with statistical models.” All of the genes of the Scotland cohort have been identified, so a computer program can scan each person’s DNA and identify which people have one or more of the high-risk genes. “Since these people in Scotland have been followed for 10 years, we know who has developed stroke over this time,” says Pola. The model shows that the greater the number of high-risk genes a person with diabetes has, the higher that person’s risk of developing myocardial infarction or stroke. Pola plans to test this model with other diabetic populations in the United States.

Pola welcomes collaboration in his lab’s areas of expertise, primarily in techniques related to the study of angiogenesis in vitro and in vivo. He also says the animal facility at the Center for Cardiovascular Research has the capacity for expanded usage. Pola would like to find a collaborator in sleep apnea and the neurological effects of sleep apnea, which causes intermittent hypoxia. “We have some interesting findings related to molecular mechanisms that are activated in the brain in response to hypoxia, and we would like to follow these preliminary findings with somebody whose experience and equipment could help us study this phenomenon,” says Pola.

For more information, please go to CSEMC Research and

Dr. Pola can be contacted at Roberto.Pola@tufts.edu and (617) 562-7275.



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