Newswise — Evgeny A. Nudler, Ph.D., Professor of Biochemistry at New York University School of Medicine has received the prestigious Director's Pioneer Award from the National Institutes of Health (NIH). "The Pioneer Award supports exceptionally creative scientists who bring their talents, expertise, and perspectives to bear on some of the biggest challenges in biomedical research," says Dr. Elias Zerhouni, Director of NIH.
"I didn't expect to even be a finalist," says Dr. Nudler. "I very much appreciate receiving the award." The award provides Dr. Nudler $2.5 million support for his research over five years.
"What we have proposed is to create conceptually new types of antimicrobials and vaccines," says Dr. Nudler. Because neither of these drugs classes is a popular area of industrial research and development, academic researchers must fill the gap, he says. While his ongoing work has led to important basic research discoveries, he wants to work on additional projects that can potentially help treat or prevent infections in the not too distant future.
Bio-Sketch
Evgeny A. Nudler received his Ph.D. in biochemistry in 1995 from the Institute of Molecular Genetics in Moscow, Russia. Among his previous awards are a Searle Scholar Award and an Edward Mallinckrodt, Jr. Foundation Award. He also has a Black Belt in the Japanese martial art of Shorinji Kempo. In recent years, he says, he has had less time for training. His workday is about to get busier still.
Dr. Nudler and the ten scientists in his lab have worked on several different types of complex biological questions, and found novel answers in each case. As he continues that research as well as his two new ventures, Dr. Nudler plans to use the award to apply his expertise in bacteria to create platform solutions for a wide range of biomedical challenges.
Dr. Nudler's plans for using the Pioneer Award: 1) New approach to vaccines2) Antimicrobials venture
1) New approach to vaccines
With the Pioneer Award, Dr. Nudler and his group plan to develop heat-stable vaccines. Vaccines are usually parts of microbes that have been killed or weakened. Vaccines are expensive to make, usually need to be injected, and are difficult to store. For example, they must be kept refrigerated at all times prior to injection, which is often an impossible task in developing countries, says Dr. Nudler. Vaccines based on his ideas may not face those challenges.
These new vaccines involve the mucosal immune system. Mucous membranes such as the linings of the gastrointestinal, urogenital, and respiratory tracts are the ports of entry into the body for pathogens such as the flu virus. Although 80 percent of the body's response to invaders is through the mucosal immune response, most vaccines do not target this very first contact between a pathogen and the host. "If someone learned how to potentiate [in other words, strengthen.] this immune response it could prevent numerous infections," says Dr. Nudler.
"One idea we have decided to pursue uses the bacterial spore," he says. Under adverse conditions, for example a lack of nutrients, bacteria produce protective cocoons called spores. Spores don't have a shelf life. "They can live forever," says Dr. Nudler. When the conditions change for the better, the bacteria germinate and thrive.
Dr. Nudler believes spores can be used as vaccine ferries. Antigens, proteins that provoke an immune response, would be the bacteria's payload. "Bacteria can be designed to display or express an antigen, and thus direct the immune response," he says. In this way, bacterial spores could be used as a vehicle for various antigens, thus fighting many different kinds of pathogens. The spores could also be geared to express the body's own antigens, so-called auto-antigens, which play a role in autoimmune diseases. Delivering auto-antigens via the mucosal surface can, among other things, slow down or even stop the progression of autoimmune disorders.
To establish proof of principle for this approach to vaccines, Dr. Nudler and his lab is experimenting with B. subtilis, a benign soil bacterium that is used in foods, for example, in yogurt cultures.
2) Antimicrobials venture
The other Pioneer Award project in the Nudler lab will involve development of novel types of antimicrobials. In past work he has synthesized tailored chemicals that can react in concert with nitric oxide (NO) to deactivate bacterial enzymes.
Nitric oxide levels are always higher in infected areas of the body because cells of the immune system, such as macrophages, produce NO to combat and kill bacteria. Dr. Nudler's plan is for this novel antimicrobial to tap into the power of NO and amplify it.
Much work remains to be done to develop the right kind of small molecule, says Dr. Nudler, but past research in his lab has shown that the concept can work. "For bacteria it is very difficult to acquire resistance to these types of chemicals," he says. The idea is to develop a binary weapon against bacteria. "It will kill bacteria only in the presence of NO," he says.
The chemical would be designed as a prodrug, which is a drug precursor. This precursor molecule would be activated by bacteria when they try to degrade the chemical, cleaving off part of the molecule. Rather than being destructive, this cleavage would activate the chemical. Together with NO it would be able to destroy bacterial proteins that are responsible for the microbe's pathogenicity. One tricky part about NO, says Dr. Nudler, is that some bacteria appear to use nitric oxide to protect themselves and thus undermine the immune reaction. But in general he believes this approach of using a chemical plus nitric oxide looks promising.
Building on his past research
The Pioneer Award builds on Dr. Nudler's past achievements. His laboratory has been studying nitric oxide biochemistry for some time. These studies have resulted in important findings that explain how NO interacts with proteins and the role of NO in bacteria.
By developing new experimental methods, Dr. Nudler has also studied the structure and function of the enzyme RNA polymerase (RNAP), which transcribes genetic information from DNA into RNA. Dr Nudler found a biochemical ratchet mechanism that governs RNAP movement and its response to signals in the DNA that control gene expression. Transcription regulation helps an organism adapt to a changing environment and survive change.
Dr. Nudler and his coworkers also found elements in the bacterial genetic code called riboswitches, which direct the activity of groups of genes. Riboswitches act as ubiquitous RNA sensors of the environment and appear to be crucial parts of the ability of bacteria to adapt to changing living conditions.
He has also studied protective proteins that cells mobilize under stress called heat shock proteins. Despite their name, they are not just activated in heat, but in a variety of conditions including cold, exposure to toxins or lack of oxygen or water. Recent works from Dr. Nudler's lab challenge the conventional view on how heat shock proteins are regulated. The scientists discovered a complex made up of a translation elongation factor called eEF1A and a previously unknown RNA called heat shock RNA (HSR). HSR is believed to be a universal RNA thermosensor in mammalian cells.
Dr. Nudler explains that he is glad to have made discoveries in his lab that are of great importance for basic research. Explaining his motivation for his Pioneer Award application, he says: "We wanted to use our ability in various biological fields to perhaps have an impact on human health in the foreseeable future."
About the NIH Director's Pioneer Award
The NIH Director's Pioneer Award, first launched in 2004, supports scientists of exceptional creativity who propose innovative approaches to major challenges in biomedical research. It is a grant for future research that has the potential to produce an unusually high impact on biomedical research. The award is a component of the NIH Roadmap for Medical Research.
More information about the award: http://www.nihroadmap.nih.gov/pioneer.
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