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Moved into Permanent Home, SRI's CADRE Boosts Proteomics Work into Rx, Dx for Infectious Diseases

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This story originally ran on Nov. 19.

By Tony Fong

SRI International has moved its Center for Advanced Drug Research to its new permanent home as it eyes bulking up its proteomics operations.

The move to the Rockingham County Research and Technology Park in Harrisonburg, Va., will eventually provide CADRE with 40,000 square feet of space, more than 11 times the amount of space it previously had. Established in January 2007, CADRE had been housed in a 3,500-square-foot space on the campus of James Madison University. Its new facility currently has 21,000 square feet.

The remaining 19,000 square feet is expected to be finished in about a year, said Krishna Kodukula, executive director of CADRE.

CADRE moved to the new space two months ago, and a dedication ceremony was held last week.

With the move, SRI, a non-profit research institute based in Menlo Park, Calif., will now be able to fully carry out its proteomics work with the hiring of additional scientists and support personnel, as well as add new instrument platforms, Kodukula told ProteoMonitor this week. To date, CADRE, which is SRI's main proteomics research facility, has directed its research at host-vector-pathogen interactions and new methods of detecting and treating diseases.

But moving forward, additional attention will be directed to applying proteomics methods and technologies in areas such as biomarkers for antibiotic resistance and intracellular toxin transport. Researchers at the center will also combine SRI's computational tools and approaches with proteomics to develop new therapeutics and diagnostics, Kodukula said.

Current projects include the development of new drugs for tuberculosis, leishmaniasis, and dengue fever. Researchers at CADRE are also working on a diagnostic tool for aspergillosis.

Further into the future, he added, the center is interested in investigating metabolic and neurodegenerative diseases, first by detecting biomarkers for such ailments and then developing therapeutics for them.

Proteomics research, he said, can be broken into two groups — work that is directed at developing new technologies and methods; and research using technologies and methods to gain a better understanding of biology.

CADRE's efforts belong squarely to the latter group, Kodukula said.

"What we intend to do is to take the advanced techniques that are being developed by our colleagues at other sites and apply them to address some of the key, critical disease-related issues," he said. "I am looking at breaking open the disease paradigm, [to investigate] what happens, what the markers are, how they correlate with disease — is there up-regulation, down-regulation — things like that."

The new facility is outfitted with a 4800 Plus MALDI-TOF/TOF platform and a QStar LC-MS/MS instrument, both from Life Technologies' Applied Biosystems division. Kodukula and his staff are in the process of acquiring an Orbitrap platform from Thermo Fisher Scientific and are shopping for two additional nanoLC platforms. They already have one such instrument and an HPLC system.

CADRE is also building out its staff as it ramps up it proteomics work. At the time it moved out of its JMU space, it had 14 employees. It currently has 18 and Kodukula anticipates adding six more employees by the end of the first quarter of 2010.

By the end of next year, it hopes to have about 40 to 45 workers, the vast majority of them researchers, Kodukula said, and by the end of 2012, the goal is to be fully staffed with 100 people, comprised of 80 to 85 scientists.

As it increases its staff, CADRE is looking to fill positions along the entire proteomics workflow, including mass spectrometrists, protein biochemists, and structural biologist as well as computational biologists, parasitologists, molecular virologists, and others who can translate proteomics data for different applications.

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'End-to-End Proteomics'

Before CADRE was established, SRI had conducted research in the proteomics space, mainly in neurobiology with a particular emphasis in sleep disorders, "but it was at the rudimentary stage," Kodukula said. He added that "the full end-to-end proteomics capability [happened] only after establishing CADRE."

While the disease areas that CADRE is researching don't lack for attention from the scientific community, in general, "a lot has been done in the conventional way," he said, and the thought is that proteomics will "help us find better insights into these very complex disorders."

The main research focus, so far, has been on host-vector-pathogen interactions in insect-borne viruses, respiratory and diarrheal pathogens, and parasitic protozoa.

"It's a three-pronged problem: The proteins that are activated when an insect bites and transmits a pathogen, and the way a pathogen infects the insect and survives within the insect before it goes into a vertebrate host," Kodukula said. "So the proteins involved in all of these protagonists … are critical to understand, and there has been little that has been done in early stage infections in applied proteomics."

One reason for that is that the genomes for the bugs responsible for transmitting the diseases have only been recently sequenced. Also, some diseases that once were considered under control in developed nations are now re-emerging as threats due to increased travel to and from less-developed nations, he said.

"We need to go back and look at this in a fresh way," he said. "That's why we are doing this."

In a statement, CADRE said it also is doing discovery work targeted at a novel insecticide aimed at infection-carrying mosquitoes as a preventive treatment.

While it has applied for funding from the National Institutes of Health and the US Department of Defense and received "very encouraging signs that some of [our projects] may get funded," the center's work is primarily being funded internally.

CADRE's proteomics research is still in the early stages, but its top priority is a project investigating antibiotic resistance in tuberculosis. The project was funded by a $100,000 Grand Challenges Explorations grant from the Bill & Melinda Gates Foundation. The center's researchers have identified potential pathways to target, but Kodukula declined to comment on it.

The aim is to eventually develop new therapeutics for the disease. Similarly, CADRE's research into leishmaniasis and dengue fever is directed at therapeutics development.

Its diagnostics work is targeted at aspergillosis, a fungal disease commonly contracted by people with immunocompromised systems, such as those undergoing chemotherapy and people taking immunosuppressive drugs.

"If it is not detected rapidly, the fatality rate is extremely high," Kodukula said. CADRE is working with collaborators from the University of Cincinnati on a chemical-biology platform based on fluorescence for detection of the disease. Since it kicked off eight months ago, "we have started to see some very promising preliminary data, so probably by the end of next year, we'll have something very good to report," he added.

The center's current work into hematologic diseases may also lead to new diagnostics, he said. Pointing to home pregnancy tests as "the gold standard for diagnostics," Kodukula said CADRE is "aiming all our assays" to be similarly cheap, sensitive, rapidly deployable, and easily disposable.

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