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NHLBI Awards $83.5M to Seven Institutions for Proteomics Research in Cardiovascular Diseases

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By Adam Bonislawski

The National Heart, Lung and Blood Institute last week awarded contracts totaling $83.5 million to seven institutions for proteomics research into cardiovascular diseases.

The awards are part of NHLBI's newest proteomics program, which seeks to "understand the mechanisms that underlie many of the clinical questions related to heart, lung, and blood disease," Pothur Srinivas, a program director at NHLBI, told ProteoMonitor.

The contracts, which are for five years and will be reviewed on an annual basis, went to Boston University; Johns Hopkins University; Massachusetts General Hospital; Stanford University; the University of California, Los Angeles; the University of Texas Health Science Center; and the University of Texas Medical Branch at Galveston.

The program, which the institute announced in January 2009, seeks to build on work done in two earlier NHLBI-funded proteomics initiatives – the Clinical Proteomics Program, which focused on developing clinical validation methods for proteomic research, and the Proteomics Initiative, which was aimed at developing new technologies for proteomics studies.

Four institutions participated in the clinical program, which launched in 2005 and ended in June 2009: the University of Colorado specifically looked at biomarkers for lung disease; the Mayo Clinic tackled biomarkers of vascular disease; Massachusetts General Hospital focused on biomarkers for myocardial injury; and the Vanderbilt University Medical Center worked on biomarkers for acute respiratory distress syndrome.

The NHLBI Proteomics Initiative, which began in 2002 and expired in September 2009, had 10 participating centers: the Boston University Cardiovascular Proteomics Center; Johns Hopkins Proteomics Center; Medical College of Wisconsin Proteomics Center; Medical University of South Carolina Proteomics Center; Seattle Proteome Center; Stanford University Proteomics Center; Uniformed Services University Medical Proteomics Center; University of Texas Medical Branch, Galveston; University of Texas Southwestern Medical Center, Dallas; and the Yale Proteomics Center.

The current initiative will combine the results and goals of these two programs, Srinivas said, focusing on "technology development, but in the context of trying to understand the molecular mechanisms of clinical issues," with each team "focusing on a distinct clinical question."

Ultimately, Srinivas said, the program aims to develop clinically validated assays useful in the diagnosis and treatment of cardiovascular disease. The teams, he said, are beginning with "very crude assays," that will be refined and developed through the research done in the initiative.

"It's a combination of technology [development] and validation," he said. "So if there's something they see [that is] reproducible, the hope is that they can come up with assays that can be validated and be useful to the broader community."

Garry Nolan, an associate professor of microbiology and immunology at the Stanford School of Medicine, told ProteoMonitor that he expects his group's work to "build heavily on the advances of the last contract", of which he was also an awardee.

That work, which focused on understanding how autoimmunity relates to cardiovascular diseases, led to the development of a test for rheumatoid arthritis that was licensed to Roche Diagnostics; microfluidic technology for the analysis of various immune mediators; and two companies — Nodality, a diagnostics development firm, and Cytobank, a flow cytometry computer analysis company (PM 03/09/2009).

This time, Nolan's team will investigate pulmonary arterial hypertension, working under the hypothesis that "a significant, if not majority, of PAH cases are auto-immune or based on pathogen-based inflammatory initiators," he said.

The research will use the tools developed through the last contract and apply them to the study of PAH, Nolan said, adding that PAH thus far "has undergone little to no deep scrutiny by the immunology community as a whole."

Moving to the Clinic

Nolan suggested that the NHLBI programs had pushed scientists to consider more seriously what is needed to make their work clinically applicable.

"Researchers are realizing that if you want to do good clinical biology in a research setting, you need to rethink your tool set and how you apply it to clinical samples," he said.

To that end, one of the program's goals, Srinivas said, is developing standards and methods to ensure better reproducibility for proteomic research across labs and platforms. The lack of high-quality reagents – especially antibodies – and poor reproducibility of quantitative mass spectrometry data are a few issues the institute hopes the researchers will tackle.

"The goal is that [the centers] will collaborate. Especially for validation it would be good if the centers help each other out seeing if the results are true across platforms," he said.

Merry Lindsey, associate professor at the University of Texas Health Science Center, echoed Srinivas' sentiments, telling ProteoMonitor that the UTHSC team had scientists from several of the other awardees, including Boston University and Johns Hopkins, on its advisory board.

"My intention is to involve them along the way," she said. "So there will be lots of opportunities where they can measure things in their samples that we find and vice-versa."

The UTHSC researchers are examining peptides found in cardiac extracellular matrix with the goal of developing blood-based biomarker signatures that can be used in the assessment of heart attack patients and measuring their progression to heart failure.

The team already has initial data suggesting that "collagen and fibronectin are going to be key extracellular matrix proteins," Lindsey said, and aims at the end of the five years "to have identified a candidate panel of ECM peptides that will have predictive capabilities.

"Once we have a list of peptides, then we can look at drugs that would target those peptides in a beneficial way to affect the course of outcome," she said, adding that she thought proteomics researchers were "very close" to developing clinically useful assays for cardiovascular diseases.

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