An Oklahoma Medical Research Foundation scientist has been awarded a five-year, $1.8 million National Institutes of Health grant to study a specific glycoprotein that has proved crucial in healthy blood vessel development in the brain.
Research scientist Lijun Xia, M.D., Ph.D., was awarded a grant to investigate how this protein, called podoplanin, assists with healthy blood vessel development and structure to prevent bleeding.
Despite making up only 2 percent of our total body weight, the brain receives 15-20 percent of the body’s total blood to supply ample nutrients and oxygen. To function properly, the brain must develop a sophisticated blood vessel system. This also makes it ideal for study.
“The brain is very sensitive to oxygen deficiency and bleeding,” said Xia, who holds the Merrick Foundation Chair in Biomedical Research at OMRF. “This organ has the richest vessel network in our body, and that vessel network needs to develop in a regulated order to function properly.”
Xia’s lab at OMRF discovered that podoplanin was highly expressed during blood vessel development in the brains of mouse embryos. Interestingly, these high podoplanin levels were uniquely made in the brain, while hardly at all in other organs.
When the podoplanin was deleted, the mice developed defective vessels and also suffered from significant brain bleeding.
“This shows that podoplanin is essential to the proper development of the brain’s vessels,” said Xia. “Without it, the vessel doesn’t develop well, and its structure is poor and leaky. Podoplanin clearly is paramount for healthy vessel function in the brain.”
That discovery, said Xia, ultimately led to the grant award, but he is also looking into how podoplanin controls this development and prevents leakage. The answers, said Xia, could have an impact in two key areas.
The first relates to germinal maxtrix-intraventricular hemorrhage, or GMH-IVH, which affects nearly 35 percent of all prematurely born babies. Due to a variety of reasons associated with premature birth, a high number of newborns are at risk for severe brain bleeding that leads to detrimental consequences such as cerebral palsy, seizures, paralysis or mental retardation.
“We believe our research can help in developing therapies for this condition, which is a significant healthcare issue,” said Xia. “Understanding podoplanin’s role could lead to ways to prevent it, which would be a real advancement in patient care.”
The other application occurs far further down the human timeline.
Podoplanin is also expressed in the brain after birth, but Xia said preliminary data suggest that after birth, this molecule normally does nothing in a healthy adult. But when people age and start to have vessel problems, they can become more prone to stroke. That’s when this protein becomes important again.
“In a stroke model, mice without this molecule developed more significant bleeding damage because the stroke caused vessel leakage,” said Xia. “Severe consequences like this illustrate the molecule’s importance.”
By learning more about the contribution of this molecule to the blood-vessel development process, Xia said scientists can better understand how to control complications when strokes occur, limit brain bleeding afterward and also potentially reduce the risk of strokes before they happen.
“It’s a project with potentially significant implications for detrimental conditions brought on by this bleeding or leakage and poor vessel structure in the developing brain, as well as the aging brain,” he said.
The grant, number 1R01HD083418-01, was awarded by the National Institutes of Health and supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development.
