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Using NIH Roadmap as Guide, NIGMS Hopes Imaging Probe Proposal Will Improve HT Cell-Based Assays


The National Institutes of Health is soliciting proposals for new molecular imaging probes to facilitate cellular microscopy, according to a program announcement released at the beginning of this month.

Although the program announcement is intended to foster the development of probes that will increase the efficiency of basic research microscopy, the NIH expects that many of the resulting technologies will be parlayed into improved methods for high-throughput and high-content drug screening, an NIH official told CBA News this week.

The National Institute of General Medical Sciences is coordinating the grant administration, and seeks to "evaluate promising but unproven enabling technologies for the routine detection by microscopy of single molecules and single molecular events inside cells," according to the program announcement, released on March 29.

The funding is open to for-profit and non-profit entities, and the first cut-off date for application receipt is May 25, with an optional letter of intent due on April 25. The program will continue through the summer, with an additional application deadline of Aug. 29 and letter of intent deadline of July 29.

Applications will be reviewed over the fall and winter, and the earliest anticipated start dates will be April 1 and July 1, 2007, according to the NIH. The full program announcement, entitled "Molecular Probes for Microscopy of Cells," can be seen here.

"Things like technologies for packaging and delivering probes to cells, we think in the long term could have a high impact for things like high-throughput screening."

James Deatherage, a coordinator in the division of cell biology and biophysics at NIGMS, told CBA News this week that the program announcement is in the same vein as the NIH's Roadmap for Biomedical Research initiative or Molecular Libraries Screening Center Network, though is not officially affiliated with those programs.

"There is a set of Roadmap principles, and it's based on those in its design," Deatherage said. "It has interdisciplinary aspects, and it's a high-risk, high-payoff type of activity. However, administratively, it is not associated with [the Roadmap or MLSCN]."

Deatherage said that NIGMS chose to proceed with this project, however, because of the intended general applicability of the sought-after technologies. "We decided to go ahead with this because the Roadmap activities tend to be of more trans-NIH interest," he said. "We're most interested here in technologies that you'd apply to image single cells in a basic research context, and that's of less general trans-NIH appeal."

This is not to say, however, that the technologies couldn't eventually be applied to high-throughput or high-content cell-based screening applications.

"We think there will be spin-off benefits, but the lead goal, which is that very high detection sensitivity, will be especially useful for basic research," Deatherage said. "But things like technologies for packaging and delivering probes to cells, we think in the long term could have a high impact for things like high-throughput screening.

"If we could make some of these things work, they would open up a whole new class of assays that could be used for screening purposes," he added.

In fact, NIGMS had previously sponsored a similar RFA that was, according to Deatherage, based on Roadmap principles, but was prior to the establishment of the Roadmap. This RFA, entitled "Development of High-Resolution Probes for Cellular Imaging," was a more general probe-development program that the Roadmap subsequently took over and turned into its first RFA.

Many of the technologies funded through that program are now being explored for high-throughput or high-content screening applications. Particular examples include the development of quantum dot technology by Sanford Simon at Rockefeller University and Shuming Nie at Emory University.

NIGMS also helped coordinate a follow-up RFA, called "Innovations in Molecular Imaging Probes," which carried a restriction that the probes had to have clinical potential. The most recent PA does not have such a restriction.

Deatherage said that the most recent PA is intended to spur the development of more general molecular probes. However, the NIH does have some specific ideas in mind. Foremost, it hopes to stimulate the development of new classes of molecular imaging probes that produce a higher signal output and are more specific for cellular targets than currently available probes.

"If you were in a satellite, and wanted to see where people are, for instance, in New York City, each person could carry a tiny light on their head, and you'd see a general diffuse glow," Deatherage said.

"If we could instead put a 1,000-watt light on a person's head, and instead of labeling everybody in New York City, put it on the heads of 50 people, we could see 50 really bright lights separated from each other, and follow them individually, and that's much more informative," Deatherage added. "So instead of labeling thousands of molecules in a cell and looking at them all together as a blur, you would deliberately underlabel, so only a handful of the molecules produce a signal and you could follow them individually."

Furthermore, the NIH hopes to stimulate research on methods for packaging and delivering molecular probes to cells, a "non-trivial problem," according to Deatherage.

"If you're working with an antibody with a dye on it, there is no good way to get it into the cell — you basically have to micro-inject it with a needle," he said. "With GFP, the delivery is perfect, because you express it genetically. If you have something like a quantum dot, and it's outside the cell, it gets taken up by endocytosis and ends up in the lysosome, which isn't very interesting. If you inject it with a micropipette, you've got to perturb the cell, which can traumatize it."

According to the PA, the NIH is also interested in funding "basic research on underlying fundamental photophysical phenomena relevant to improving the spectral properties of fluorescent probes."

Grants will be awarded following the R01 grant mechanism, in which awards are not limited in dollars, but need to reflect actual needs of the proposed project. Applicants requesting up to $250,000 per year in direct costs must submit proposals in a modular format using $25,000 modules. Applicants requesting more than $500,000 in direct costs in any year must include a plan for sharing research data.

Deatherage said that the NIH doesn't have a figure in mind for total available funding, adding that it "intends to maintain a quality cut-off that compares to the rest of our portfolio." He said the institute is expecting to award anywhere between four and 12 average-sized grants, though much depends on the quality of the applications.

— Ben Butkus ([email protected])

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