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NIAID Adds Biodefense Proteomics Contracts, Bringing Program Funding Up to $90 Million

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Earlier this month, the National Institute of Allergy and Infectious Diseases awarded two additional five-year contracts for biodefense-related proteomics to groups at Harvard Medical School and Caprion Pharmaceuticals.

Together with five contracts awarded earlier this summer (see PM 7-16-04), these new awards bring the total funding for NIAID-sponsored Biodefense Proteomics Research Centers up to nearly $80 million.

These centers (see http://www.niaid.nih.gov/dmid/genomes/prc/), which are part of a broader NIAID biodefense initiative providing funding for bioinformatics, genomics, and proteomics, will analyze proteins in a number of microorganisms that could potentially be used as bioweapons. They include pathogens classified by NIAID in categories A, B, and C, as well as the SARS virus. “The goal is to discover new targets,” for developing drugs, vaccines, and diagnostics, according to Joe Breen, an NIAID program officer.

NIAID said it plans to spend about $90 million in total on the program, but did not say whether it will award any more contracts in the near future.

ProteoMonitor caught up with the current seven contractors to find out about their research plans.

Albert Einstein College of Medicine

Albert Einstein College of Medicine received $10.9 million in funding to find new therapeutic targets in two waterborne parasites, Toxoplasma gondii and Cryptosporidium parvum.

Under the direction of George Orr, a protein chemist and professor of molecular pharmacology, six research groups at Albert Einstein plan to identify membrane-bound protein complexes, as well as proteins mediating the association of the cytoskeleton, using both LC-MS/MS and MALDI mass spectrometry. They will then validate the potential of these proteins as targets for drugs or vaccines by gene ablation and other techniques. The groups, which will obtain a separate laboratory for the project at Einstein, also plan to develop new proteomic and bioinformatics methods to determine which protein domains are physically interacting and to relate this data to structural information, according to Orr. Unlike the other contractors, this group will have no outside collaborators. “We are self-contained within Einstein because we had all the necessary expertise,” Orr said.

Caprion Pharmaceuticals

Caprion Pharmaceuticals of Montreal, Canada, was awarded a $13.1 million contract to study molecular events that enable bacteria to subvert the immune system. The project will define new pathways and proteins that can lead to new immunotherapy targets, vaccines, and diagnostic biomarkers.

Caprion will employ its quantitative protein profiling technologies to analyze pathogen and host proteins involved in infections by Brucella abortus, a potential bioterrorism agent that also causes disease in cattle. The company will use LC-MS/MS to analyze proteins that are over- or under-expressed when a cell is in a diseased state.

Caprion will collaborate with Michel Desjardins’ research group at the University of Montreal in studying Brucella. Dasjardins is an expert in the study of intracellular pathogens and has worked with Caprion to study host defense systems.

Harvard Medical School

Under the direction of principal investigator Joshua LaBaer, the founder and director of the Harvard Institute of Proteomics at Harvard Medical School, researchers will use $12.4 million worth of funding to build gene repositories for Bacillus anthracis, the causative agent of anthrax, and Vibrio cholerae, which causes cholera.

After building gene repositories for the two organisms, the researchers will use expression clone arrays to express proteins in situ. They will then analyze the proteins to identify potential therapeutic targets for vaccines.

“We put the genes in vectors, and then we print the DNA on a chip,” explained Leonardo Brizuela, one of LaBaer’s co-investigators. “Then we transcribe and translate the DNA with some tricks to produce captured proteins.”

LaBear and Brizuela have already built gene repositories for several hemorrhagic viruses, as well as Yersinia pestis, the causative agent of bubonic plague, and other pathogens targeted for study by the NIAID. They chose to hone in this time on Bacillus anthracis and Vibrio cholerae because the researchers they are collaborating with at Harvard Medical School and Massachusetts General Hospital are leaders in the fields of anthrax and cholera.

Myriad Genetics

As previously reported (see PM 7-16-04), Myriad Genetics won a $14.2 million contract to analyze human-pathogen protein interactions using its high-throughput yeast two-hybrid platform.

Led by Karen Heichman, the company’s vice president of proteomic research, Myriad researchers and four academic collaborators will study Bacillus anthracis, Yersinia pestis, Francisella tularensis, and vaccinia virus (the company dropped its plan to study C. botulinum).

Initially, Myriad will screen every protein from each pathogen against a library of human proteins derived from different tissues, mostly immune cells. In a second screening round, the company will focus on a number of interesting proteins to study their interactions with human proteins in more detail.

The collaborators are Martha Furie and James Bliska at SUNY Stony Brook, Kenneth Bradley at UCLA, and Grant McFadden at the Robarts Research Institute in Canada, are each an expert in one of the four organisms and will validate the data biologically.

Scripps Research Institute

Peter Kuhn, an associate professor of cell biology at Scripps, and his research group plan to use $14.3 million in NIAID funding to investigate the structure and function of SARS virus proteins.

Kuhn said his research group will be using primarily X-ray crystallography, nuclear magnetic resonance spectroscopy, and electron microscopy to investigate the three-dimensional structures of SARS proteins.

Kuhn will be working closely with Michael Buchmeier, the principal virologist of the group. The scientists aim to figure out the functions of SARS proteins within the life cycle and to identify potential targets for therapeutic intervention. At this point, the proteins of the SARS virus have been identified, but not their functions, Kuhn said.

“This is a very systematic approach,” said Kuhn. “We are at this point very much at the basic structural proteomics and functional level.”

Outside of Scripps, Kuhn’s group will be collaborating with the Burnham Institute, which will perform bioinformatics analysis, and with the Palo Alto Research Center, which will perform enthalpy measurements for protein-protein and protein-ligand interactions.

University of Michigan

The group of Philip Hanna, an anthrax expert and assistant professor of Microbiology and Immuno logy at the University of Michigan, won $6 million to study protein expression in Bacillus anthracis, in collaboration with John Yates’ group at the Scripps Research Institute.

The aim is to determine the expression of genes and proteins from B. anthracis as well as host cells at every stage of an anthrax infection.

Hanna’s group will provide samples from models of infection, analyze gene expression using custom-designed Affymetrix microarrays, and analyze the data by bioinformatics. Yates’ group at Scripps, which will receive about $2.2 million of the funding, will analyze protein expression using its tandem LC-MS/MS shotgun proteomics approach. John Quackenbush at the Institute for Genomic Research is an advisor to this project.

Social & Scientific Systems

SSS will join with the Virginia Bioinformatics Institute and Georgetown University to provide administrative support for the Biodefense Proteomic Research Centers. The organization has been awarded $8.7 million worth of funding.

SSS plans to develop and maintain a publicly accessible web site that will contain data and techno logy protocols generated by each center. SSS will also assist in establishing a Scientific Advisory Committee that will impart proteomic and bioinformatics expertise to NIAID.

The SSS team will also promote awareness throughout the scientific community of the Proteomics Research Program and the resources available through the program.

— JK and TSL

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