SDSC to Participate in UCSD-Led Consortium to Map Metabolic Pathways in Cells

Published 08/21/2003

The University of California, San Diego (UCSD) will lead an ambitious national effort to produce a detailed understanding of the structure and function of lipids - cellular fats and oils implicated in a wide range of diseases, including heart disease, stroke, cancer, diabetes and Alzheimer's disease.

The five-year, $35 million grant from the National Institute of General Medical Sciences (NIGMS) will support more than 30 researchers at 18 universities, medical research institutes, and companies across the United States, who will work together in a detailed analysis of the structure and function of lipids. The principal investigator of this collaboration is Edward Dennis, Ph.D, professor of chemistry and biochemistry in UCSD's Division of Physical Sciences and UCSD's School of Medicine.

Dennis notes that while sequencing the human genome was a scientific landmark, it is just the first step in understanding the diverse array of systems and processes within and among cells. Establishment of this consortium is a significant step in an emerging field called "metabolomics," or the study of metabolites, chemical compounds that "turn on or off cellular responses to food, friend, or foe," he explained.

Lipids are a water-insoluble subset of metabolites central to the regulation and control of normal cellular function, and to disease. Stored as an energy reserve for the cell, lipids are vital components of the cell membrane, and are involved in communication within and between cells. For example, one class of lipids, the sterols, includes estrogen and testosterone.

The initial phases of the project, known as Lipid Metabolites And Pathways Strategy (LIPID MAPS), will be aimed at characterizing all of the lipid metabolites in one type of cell. The term "Lipidomics" is used to describe the study of lipids and their complex changes and interactions within cells. Because this task is too extensive for a single laboratory to complete, researchers at participating centers will each focus on isolating and characterizing all of the lipids in a single class. This information will then be combined into a database (at http://www.lipidmaps.org) to identify networks of interactions amongst lipid metabolites and to make this information available to other researchers. Shankar Subramaniam, Ph.D., lead of complex systems in the San Diego Supercomputer Center's Integrative Biosciences Program and professor of chemistry and bioengineering at UCSD's Jacobs School of Engineering, will coordinate this aspect of the project.

The cell type selected for study is the macrophage, best known for its role in immune reactions, for example scavenging bacteria and other invaders in the body. Macrophage cells from mice will be used, rather than human cells, because there exists a "library" of mouse cells with specific genetic mutations. By studying cells missing certain genes, the research team will attempt to identify what genes code for those enzymes key in synthesis and processing of lipid metabolites. Christopher Glass, M.D., Ph.D., professor of cellular and molecular medicine at UCSD's School of Medicine, will coordinate the macrophage biology and genomics aspects of the consortium.

According to Dennis, one of the most difficult aspects of this project will be to ensure that all the participating research sites are using identical methods.

"There has never been an effort to detect all the lipid metabolites in a cell and to quantify the amounts of these lipids," says Dennis. "In order to be able take the data gathered by each lab and put them together to develop new ideas about interactions between lipid metabolites, it is essential to develop new technologies and methods and to standardize them so that they can be applied in the same way at each research site."

Once the researchers have developed these methods and used them to identify and quantify the lipid metabolites in the mouse macrophage, the methods can be applied to gather other information about lipid metabolites in cells. The researchers plan to study the time and dose-dependent effects of lipopolysaccharide, or LPS, a component of the cell walls of many bacteria, on macrophages. Dennis' lab has studied the effects of LPS on macrophages for the last 20 years. A world authority on these effects, Dennis says that this large-scale, cross-institutional collaboration will create an understanding of LPS' effects on lipid metabolism in unprecedented detail, and set the stage for examining other macrophage effectors such as oxidized LDL, the so-called bad cholesterol which leads to atherosclerosis.

A detailed understanding of lipid metabolism will be valuable in drug design. Most people are already familiar with one class of drugs that interfere with lipid metabolism: the non-steroidal anti-inflammatory drugs (NSAIDs), which include aspirin and ibuprofen. These drugs block the synthesis of prostaglandins, a large group of chemicals secreted by macrophages that causes pain, inflammation and an immunological response.

Statins, which a large number of Americans take daily to lower their cholesterol levels, also dramatically alter lipid metabolites. With a detailed knowledge of each step in the lipid metabolic pathways, more effective drugs with fewer side effects can be designed to combat heart disease and a plethora of other diseases of lipid metabolism.

In addition to UCSD, participants in the LIPID MAPS consortium are: Avanti Polar Lipids, Inc.; Duke University Medical School; Georgia Institute of Technology; University of California, Irvine; University of Colorado School of Medicine; University of Texas Southwestern Medical School; and Vanderbilt University Medical School. Additional collaborators will include scientists from Applied Biosystems; Boston University School of Medicine; Harvard Medical School; Medical College of Georgia; Medical University of South Carolina; National Jewish Medical and Research Center; Scripps Research Institute; University of Michigan Medical School; University of Utah; and Virginia Commonwealth University.

For more information on the grant program, see the related release at http://www.nigms.nih.gov/news/releases/