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Extending Grant to Study Emerging Infectious Diseases
Drs. Wayne Schultz and Timothy Umland have been studying the SARS virus proteins required for virus replication, since 2004. This grant was used to study the structures of the proteins that form the SARS-CoV replicase complex. Drs. Wayne Schultz and Timothy Umland recently received a new grant totaling $100,000 from the William G. McGowan Charitable Fund. They also received a grant from the National Institute of Health totaling approximately $600,000. These new grants will be used to continue their research. Specifically, these grants will help us better understand how a virus interacts with its host, human cells, and how it is able to jump from an animal to a human. These grants are intended to produce the groundwork needed to acquire federal funding for future studies.
Working to Create Safer Arthritis Medications
Recently, new arthritis medications have been taken off the market due to adverse side effects. Dr. Michael Malkowski is working to provide insight into how non-steroidal anti-inflammatory drugs (NSAIDs) affect the inflammatory process. This also may lead to the development of new medications to treat rheumatoid arthritis, osteoarthritis, and other inflammatory disease with fewer side effects. This project was awarded a three-year, $225,000 Arthritis Investigator Award from the Arthritis Foundation. Recently, Dr. Malkowski received a $1.7 million grant from the National Institutes of Health in support of his work to understand the biological processes that occur as the human body reacts to anti-inflammatory medications.
Developing New Antibiotics for Infectious Diseases
In recent years, infectious diseases have become more difficult to treat with antibiotics, as antibiotic resistance becomes an increasing public health problem. Dr. Andrew Gulick received a five-year National Institutes of Health grant award totaling $1.4 million that will attempt to determine the structures of bacterial proteins involved in antibiotic synthesis. This research will study the structure and functions of certain enzymes that synthesize antibiotics perhaps allowing the engineering of these proteins for the production of a new generation of drugs. Recently, Dr. Gulick discovered the structure of a protein from a bacteria which most frequently causes infection and death in cystic fibrosis patients. Disrupting the function of this protein prevents an important step in the establishment of an infection. We hope that this work will lead to the development of an antibiotic preventing these infections in cystic fibrosis patients. As similar proteins are present in other pathogenic bacteria, the resulting antibiotic also may have implications in other life-threatening diseases.
Expanding Our Methods Research
• For more than 20 years, our scientists have been working to build upon Dr. Hauptman’s Nobel Prize winning methods. In 2003, Dr. Hongliang Xu received a five-year National Institutes of Health grant totaling over $2 million. The main goal of this project is to develop a systematic methodology for resolving the phase problem in crystallographic computing. This work promises to lay the foundation for a new generation of crystallographic computing systems that will reveal the structure of millions of substances that are important in the understanding of life, materials science, and drug design.
• Dr. Herbert Hauptman and his team are working on the development of Neutron Shake-and-Bake (NSnB), an algorithm for the solution of the phase problem when only neutron diffraction data is available. Dr. Hauptman is collaborating on this project with colleagues from the Japan Atomic Energy Research Institute (JAERI), Ibaraki University in Japan, and the Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC) in France and has secured a grant from The Human Frontier Science Program Organization (HFSPO) to support his ground-breaking research project entitled “New Methods of Biomolecular Crystal Structure Determination Specific to Neutron Diffraction Data.” This innovative, interdisciplinary and intercontinental research project will be a collaborative effort among scientists in the United States, France and Japan.
• Dr. Michael G. Malkowski in collaboration with Dr. Elizabeth Grayhack, a yeast geneticist and research associate professor of biochemistry and biophysics at the University of Rochester, have solved a critical structural biology problem by utilizing the combined knowledge and skill set of yeast geneticists and x-ray crystallographer. Their findings have been recently published in the prestigious Proceedings of the National Academy of Sciences. Both Dr. Malkowski and Dr. Grayhack worked together to solve the dilemma of using yeast to grow the proteins needed for solving complex structures using x-ray crystallography. Dr. Grayhack and her lab were able to manipulate the yeast so that it can incorporate a heavy atom that is necessary for solving the crystal structure. Dr. Malkowski was able to grow the crystals and solve a three dimensional structure – proving that this method is successful. This discovery will make it possible to determine the structures of complex human proteins that are targets in drug development.
A Unique Laboratory
Hauptman-Woodward Medical Research Institute’s high-throughput crystallization screening laboratory transfers protein solutions from a single tube into a plate of 1536 different chemical conditions. This method of experimentation was developed by our CEO and Executive Director Dr. George DeTitta and the services of this lab are used by researchers from around the world. Since its inception, the facility has been used to conduct over 7.7 million experiments on 5000 samples provided by 550 investigators from around the world. One of ten nationally funded centers that are part of the NIGMS Protein Structure Initiative, this lab is a national center for macromolecular crystallization. This laboratory makes it possible for researchers to set up crystallization trials in less than ten minutes that would normally take weeks to set up by hand. Setting up 1536 unique crystallization experiments often provides several chemically-distinct crystallization conditions. Crystals of a protein produced in different chemical environments will often display unique physical properties that can be beneficial for downstream processing.