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Growing Tomorrow's Researchers
CHORI Associate Staff Scientists Garners First NIH Research Grant
CHORI is pleased to announce that CHORI associate staff scientist Marisa Wong Medina, PhD, has been awarded a R01 grant from the National Institute of Health (NIH) Research Project Grant Program, the most competitive and coveted granting institution in health-related research.

"It's very exciting. The R01 is the traditional grant that every researcher hopes to get," says Dr. Medina. "It's really the mark of your independence as a researcher, and as a young investigator, they are very hard to get, so I'm really very pleased."



Having worked under the lab of Ronald Krauss, MD, for the last six years, Dr. Medina is paving the way to a successful research career of her own with this, her first NIH award a five year, two million dollar grant to explore a novel mechanism of intracellular cholesterol regulation.
“CHORI as an organization is uniquely friendly to young investiga-
tors launching an independent career.”
"CHORI encourages anyone, regardless of their position, to write a grant." says Dr. Medina. "In addition, the community as a whole, and Dr. Krauss in particular, have been instrumental in supporting my efforts."

The grant, called Alternative Splicing in Regulation of Cholesterol Synthesis and Uptake, focuses on investigating whether or not alternative splicing is a novel mechanism that regulates cellular cholesterol homeostasis – and ultimately, cholesterol levels in the blood.

"Cells can obtain cholesterol from two different sources, they can make it themselves, or uptake it from the blood," Dr. Medina explains. "If there is more cholesterol in the blood than the cells need, the excess remains in the blood. That causes the plaque build-up, and that is why high levels of cholesterol in the blood are a problem."
While intracellular cholesterol homeostasis is not a new concept, the idea that alternative splicing might play a role in maintaining that homeostasis is.

"In order for a gene to become a protein, it has to be spliced, a process by which the introns or regions of the gene that never become part of the protein are removed, leaving only the exons the portion of the gene that actually encodes for the protein," explains Dr. Medina. "Splicing is the essential mechanism for translating the genetic code into actual proteins."

However, these splicing patterns can vary. Since most genes are comprised of a number of introns and exons, there can be variation in the splicing mechanism called alternative splicing such that portions or entire exons are removed out along with the introns, or conversely introns can be retained within the final transcript. Although researchers have known about alternative splicing for some time, it has generally been though of as a way to simply create protein diversity. Dr. Medina thinks otherwise.

"I suspect that it is a mechanism of regulation that is probably much more widely used than we realize. We've only just begun to have access to the kind of technology that allows us to identify every single transcript in a cell. Now we actually have the capability of finally understanding the actual impact that alternative splicing has on genetic variation," says Dr. Medina.

Dr. Medina hopes to use that technology over the next five years to confirm her hypothesis that alternative splicing is a novel mechanism by which intracellular cholesterol is regulated, and to identify key players, both genetic and non-genetic, that regulate alternative splicing. Preliminary data have already demonstrated that the level of intracellular cholesterol itself may trigger increases or decreases in alternative splicing, in what is referred to as a negative feedback regulatory mechanism. Ultimately, however, Dr. Medina hopes to correlate her genetic findings with clinical outcomes.

"In the end, we really want to bring all of this back to the physiologic relevance and ask, OK, now that we have identified this novel mechanism, how is it important to human health and human genetic variation?" says Dr. Medina.

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Tuesday, May 17, 2011 8:19 AM

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