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Finding the Next Frontier
CHORI Researchers Win Accolades at Gordon Research Conference

"Our work is controversial in some ways, because it addresses one of the largest problems in our field - the structure of the primary protein component of HDL, apoli-protein A-I."

CHORI scientist Michael Oda, PhD, and a post-doc from his lab, Giorgio Cavigiolio, PhD, both garnered significant kudos at this year’s Gordon Research Conference on Lipoprotein Metabolisms, a biannual conference that brings all the primary investigators in the field together. There, Dr. Cavigiolio won the award for best poster presentation, and Dr. Oda, for best short presentation, honors which speak to the rigor of research conducted in the Oda lab at CHORI’s Center for the Prevention of Obesity, Cardiovascular Disease & Diabetes.

“I think of it as a big honor that we were chosen by our peers for these awards,”Dr. Oda says.

The overall objective of the Oda lab is to investigate high density lipoprotein (HDL) structure and function. This involves examining the effect of HDL size, shape, and composition on the structure of apoliprotein A-I (apoA-I) and the effect of apoA-I structure on HDL function.

"Understanding this interplay between apoA-I structure and HDL function is very important from a clinical perspective, because a comprehension of apoA-I structure and function could explain the root of a variety of HDL-related metabolic issues and their clinical presentations," says Dr. Oda.

The research for which Drs. Oda and Cavigiolio won their awards focused on how apoA-I structure facilitates HDL function. HDL, known as the good guy in maintaining healthy cholesterol, withdraws cholesterol from cells and transports it via the liver either out of the body, or to those sites in the body that functionally require cholesterol. Yet HDL can only do its job with the help of apoA-I.

"To envision the effect of cholesterol on HDL, imagine a truck that, as you fill it, changes shape. Unloaded, it's small and compact, but once it assumes its cargo, it becomes large and bloated. ApoA-I, as the main structural scaffold of HDL, has to adapt to changes in HDL's shape." Dr. Oda explains.

In its unloaded form, HDL interacts very well with transporters that acquire cholesterol, but not as well with scavengers that take cholesterol back to the liver. In a similarly logical fashion, the reverse is true of HDL in its loaded form.
"This is intriguing because if you can program molecules to do one thing and not another, for example maintain the characteristics of the small and compact shaped HDL rather than the larger HDL, you could sidestep much of the regulatory mechanisms in the body."
As Dr. Oda explains, "This would create the potential to develop forms of HDL that are even better at removing cholesterol from dangerous areas."

The research Dr. Oda presented at the conference - that key structural elements within apoA-I were maintained on HDL of differing sizes - provided some illuminating information regarding the direction of apoA-I research and how to progress in the quest for understanding relationship between apoA-I and HDL structure.

"There has to be a regulatory element within apoA-I that reports changes in HDL shape as it progresses from a smaller, cholesterol-poor particle to a larger, cholesterol-laden particle. What we showed was that there was no significant structural change in the central region of apoA-I, which suggests that the regulatory portion of apoA-I must be in the two apoA-I regions we didn't look at - the N- and C- terminal ends."

In addition to identifying the only possible regulatory portion of apoA-I, the research goes further. As Dr. Oda points out, "ApoA-I is a very structurally dynamic molecule and it's highly unusual for a portion of this protein to remain so unaffected by HDL particle size."
As a result, Dr. Oda hypothesizes that this segment of apoA-I may actually serve as a kind of molecular fingerprint that distinguishes HDL from the multitude of other lipoproteins in the body.

"HDL has to have a unique molecular signature to define its characteristic biological function, and we believe this might be it," Dr. Oda says.

Both suggestions provide critical signposts for the future of elucidating apoA-I structure and function within HDL, as the conference awards suggest.

"It tells us where the dynamic regions of the molecule are - the end terminals - which is where regulation has to happen and where we should focus if we want to change how that regulation works," says Dr. Oda, "and it also tells us which regions essentially define HDL's molecular signature. Those regions are critical, they are the next frontier."

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Tuesday, May 17, 2011 8:19 AM

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