ARRA IMPACT REPORT:
Development of High-Throughput Technologies
Public Health Burden
Advances in high-speed computing and robotics have made it possible for researchers to perform fast, automated analyses of large numbers of substances including DNA, RNA, proteins, and other types of molecules and chemical compounds. These high-through put technologies are being used in many areas of biomedical research, including genetics and drug discovery.
NIH Common Fund ARRA Investment in High-Throughput Technologies
NIH Common Fund ARRA funding is supporting several research projects that are developing high-throughput technologies. These projects aim to further our understanding of processes underlying several different diseases, create new tools for disease detection and diagnosis, and develop new treatments by facilitating the drug development process.
- Assessing the impact of a cell’s environment: Dr. John Cooke and colleagues at Stanford University are developing techniques to assess the effects of interactions between cells and their surrounding environment, including how cues in the environment help determine what kind of cell a stem cell can become.1 Using a computer automated micro printing technique to create a large number of tiny cellular environment models, they have found that gelatin, a component of some extracellular environments, guides stem cells towards becoming cells of the nervous system and skin.2 Dr. Cooke and colleagues have also developed a high-throughput assay to identify compounds that can regulate dimethylarginine dimethylaminohudrolase (DDAH), a biological signaling molecule that regulates levels of nitric oxide levels in the body. Abnormal nitric oxide levels may play a role in atherosclerosis, hypertension, insulin resistance, sepsis, migraines, and some types of cancer.Thus,screening for this biological signaling molecule, DDAH, may prove useful to test large numbers of potential drugs that could alter its levels, and thereby nitric oxide levels, in a wide variety of diseases.3
- Rapidly distinguishing different bacterial strains: Dr. Cameron Currie and colleagues at the University of Wisconsin-Madison and Harvard are developing high-throughput assays to identify small molecules derived from untapped natural sources that have anti-infective potential.4 Dr. Currie and colleagues have developed high-throughput technologies that can rapidly distinguish between different bacterial strains and can help prioritize promising candidates for new natural product development.5,6
- Screening for compounds to combat malaria: Dr. David Fidock and colleagues at Columbia University Health Sciences are developing high-throughput assays to screen for compounds that target the parasite that causes malaria.7 They have developed a screen to identify antibiotics that interfere with a part of the malaria parasite called the apicoplast. Antibiotics targeting the apicoplast result in the death of the progeny of treated parasites, rather than the original parasite itself. Using this screen, the researchers discovered that kitasamycin, an antibiotic, has novel antimalarial properties. This research can be used to identify novel therapeutics that may be useful for treating malaria and can also provide insight into the unusual biology of apicoplasts.8
National Institute on Drug Abuse (NIDA) ARRA Investments in High-Throughput Technologies
- High-resolution genetic mapping using the mouse diversity outbred population.9,10 Using ARRA funding, Dr. Abraham Palmer and researchers at the Jackson Laboratory in Bar Harbor, ME have developed a new mouse strain that is more genetically diverse than any other mouse population. The genetic diversity of this resource will enable more complex trait analyses to be conducted in mice to better keep pace with rapid developments in human genetic studies. For example, the researchers were able to map a blood cholesterol trait to a tiny region on a chromosome. A genetically diverse mouse resource could accelerate discovery of the genetic basis for disease and may have other applications, including screening during drug development for rare genetically based adverse effects.
- Nicotine response genetics in the zebrafish.11,12 Dr. Stephen Ekker and investigators at the University of Minnesota and the Mayo Clinic used ARRA funding to develop a nicotine behavioral assay in zebrafish, an emerging vertebrate model system for understanding the genetics of behavior, to study the response to nicotine in genetically altered wild-type animals and strains. Genes were altered using a method that generates mutant alleles that can then be deactivated. Using this method, they identified two mutations associated with an altered nicotine response. Since the mutations have known human counterparts, they represent potential targets for developing new diagnostic kits and/or cessation medications. This zebrafish mutagenesis approach, in the context of behavioral testing, provides a powerful platform for investigating the contribution of genetic variation to vulnerability to drug addiction and other psychiatric disorders.
- NeuroPedia: neuropeptide database and spectral library.13,14 Neuropeptides are essential for cell-to-cell communication in health and disease. Understanding the role and regulation of neuropeptides requires being able to analyze neuropeptide expression, objectively and globally. Tandem mass spectrometry is the main technology for detecting neuropeptides, but the unique characteristics of many neuropeptides make it difficult to identify them when trying to interpret complex tandem mass spectrometry spectra against the backdrop of large protein databases. Using ARRA funding, Dr. Vivian Hook and a research team at UC San Diego have developed a neuropeptide database and spectral library of related neuropeptides from multiple species that is searchable using mass spectrometry data (i.e., NeuroPedia). Searching neuropeptide tandem mass spectrometry data against known NeuroPedia sequences will improve the sensitivity of database search tools and boost confidence in peptide identifications by enabling visual comparisons between new and previously identified neuropeptide mass spectrometry spectra.
Contributing NIH Institutes & Centers
- National Heart, Lung, and Blood Institute (NHLBI)
- National Institute on Drug Abuse (NIDA)
- National Institute of General Medical Sciences (NIGMS)