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NHLBI Proteomics Centers Plan to Use Plethora of Proteomics Technologies for Disease Studies

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So what proteomics technologies are you going to develop with your part of the $157 million? This is the question that ProteoMonitor put to leaders of the ten proteomics centers chosen earlier this month by the National Heart, Lung, and Blood Institute to participate in its $157 million, seven-year proteomics initiative. Following are the details on the methods each center plans to pursue:

Uniformed Services University Medical School

In his cystic fibrosis research, Harvey Pollard, professor and chair of the department of anatomy, physiology, and genetics at the Uniformed Services University Medical School in Bethesda, Md., said he had trouble correlating changes in mRNA expression levels with protein expression levels in corresponding samples. But using a “20th century” pulse labeling technique involving 35S tagging of methionine, Pollard found that protein metabolism in cells tended to more closely match the results from gene expression experiments. Pollard’s $12.7 million NHLBI proteomics contract will go toward applying this technique to cystic fibrosis.

In addition to academic collaborators, Pollard’s team will share the NHLBI contract with Apex Digital Systems, based in Silver Spring, Md., which will help develop a large-scale database of patient samples for use in discovering biomarkers and drug targets.

Medical University of South Carolina

Of the seven research projects covered under the $15.2 million award for the cardiovascular proteomics center at the Medical University of South Carolina, four are directed towards technology development, said Daniel Knapp, professor of pharmacology and director of the mass spec facility at MUSC. Knapp wants to develop a chip-based, disposable multidimensional liquid chromatography device that interfaces directly with a mass spectrometer. Other projects aim to improve 2D gel technology, especially the separation of membrane proteins, and to develop methods for analyzing intact proteins by TOF/TOF mass spectrometry. Computational analysis of protein profiles, focusing on protein interaction networks, is another focus. The center intends to purchase an ABI 4700 TOF/TOF instrument, and is planning on bidding to become the coordinating center for all ten institutions, Knapp said.

Yale University

Yale’s $18.1 million center, focusing on vascular biology, hematopoiesis, and hypertension, will involve 21 faculty members from 12 departments and will be supported by the existing HHMI/Keck Foundation biotechnology resource laboratory, according to Kenneth Williams, the core laboratory’s director. His center will focus on proteome and phosphoproteome profiling technologies, as well as methods for designing protein blocking agents, mostly peptide-based. On the protein profiling side, the center intends to improve ICAT technology, and develop methods for creating ribozyme molecular switches. Another project aims to co-develop an interoperable protein and mRNA expression database.

Institute for Systems Biology

Ruedi Aebersold, a co-founder of the Institute for Systems Biology and principal investigator for the institute’s $19.8 million NHLBI proteomics contract, said his proposal aims to expand the reach of proteomics technology in two directions: towards more automated, high-throughput approaches to analyzing complex protein samples; and towards making different types of measurements of proteomes, including properties such as phosphorylation and activation state, changes in linkages, and interactions with proteins as well as other molecules, such as lipids.

Aebersold also said the NHLBI contract will allow ISB to delve into new areas of proteomics research, including working with aptamer protein capture agents developed by SomaLogic, a Boulder, Colo.-based protein chip company.

Boston University

Catherine Costello, professor of biochemistry and director of the university’s mass spectrometry resource, said work done under her $12 million NHLBI contract will focus on proteins changed in expression or modified as a result of oxidative stress, a basic cardiovascular disease mechanism. As part of a new proteomics laboratory at BU’s medical school, she said she is planning to purchase a Q-TOF mass spectrometer and several capillary liquid chromatography systems. One project is to develop a new type of cryo-FT-ICR mass spectrometer, a high-throughput instrument that will provide information particularly on proteins modified by oxidation. A BU bioinformatics group will help develop software to control the instrument and to process its data. In addition to collaborating with about ten BU medical research groups, the center is teaming up with Beyond Genomics to use the company’s multi-stage chromato graphy technology, and with the NHLBI’s Framingham Heart Study. Costello said that her center would be willing to become the national coordinating center if asked to.

Stanford University

Garry Nolan, associate professor of microbiology and immunology, said that the Stanford proteomics center, funded with $14.9 million, will apply its technology to autoimmune diseases. Nolan’s team will map intracellular signaling systems in intact immune cells by flow cytometry, using up to 13 differently labeled antibodies that can penetrate the cell membrane in parallel. A second group will develop antigen arrays, and a third group, collaborating with Aclara BioSciences, will study cytokines using chip-based microfluidics for high-throughput capillary electrophoresis. A bioinformatics group will try to combine and analyze the data from the different approaches.

University of Texas Medical Branch at Galveston

Alexander Kurosky, professor of human biological chemistry and genetics, said his $15 million NHLBI proteomics center will include four technology and three biology groups focusing on airway inflammation. The projects involve collaborations with Ciphergen on protein arrays, Nonlinear Dynamics on 2D gel imaging and analysis software, Lynx Therapeutics on 2D electrophoretic protein separation, and Texas Biotechnology on drug targets, Kurosky said. His team will develop high-throughput cell separation and organelle separation techniques, as well as protein quantification methods; other groups will focus on antibody and aptamer arrays, protein separation technology, and bioinformatics.

Johns Hopkins University School of Medicine

Eduardo Marban, professor of medicine and physiology at Johns Hopkins University School of Medicine, said his team plans to use its $18 million award for developing proteomics technology for the study of ischemia and hypoxia, particularly as the conditions affect the heart, lungs, and blood. Along with co-director Gerald Hart, also of Johns Hopkins, Marban said his team will look to develop new approaches to studying glycosylated and phosphorylated proteins, as well as novel mass spectrometry instrumentation.

Specifically, the group plans to investigate new techniques for using UV and IR atmospheric pressure MALDI ionization techniques for studying enzymatic protein digests, new electrospray-TOF configurations for studying proteins, and methods for adding TOF/TOF capabilities to a Kratos Axima CFR mass spectrometer.

University of Texas Southwestern Medical Center

At the University of Texas Southwestern Medical Center in Dallas, Tom Kodadek is directing a proteomics center funded with $16 million to apply DNA and protein microarray technologies to the study of sleep disorders, with a particular focus on transcription factors and membrane receptors. In one area of the project, the group plans to identify several hundred G-protein coupled receptors potentially involved in sleep mechanisms in the brain, and array them onto chips for screening experiments. In another, Kodadek’s team plans to develop small molecule affinity ligands for use with microarrays. While the project will involve mass spectrometry “only peripherally,” Kodadek said, the group plans to purchase a “standard” quadrupole mass spectrometer with MS/MS capabilities.

Overall, the centers will exchange information during at least semi-annual meetings, organized by a national coordinating center, which has yet to be chosen from among the ten. This center will also establish and maintain a website for the initiative.

— JK/JSM

 

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