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Monday, October 25, 2004, 12:00 a.m. EDT
New Center to Map DNA of Key Lab Mice
RESEARCH TRIANGLE PARK, NC - The (http://www.niehs.nih.gov) will invest $13 million to map the DNA of 15 mouse strains important to laboratory research on human health. This initiative, called the "Resequencing Project" will launch the Institute's Center for Rodent Genetics.
The Center for Rodent Genetics is an extension of the Institute's ongoing research to understand the genetic basis for differences in response to drugs and other environmental factors. Other initiatives include the Environmental Genome Project and the National Center for Toxicogenomics.
"The Resquencing Project has attracted world-wide interest and generated a lot of enthusiasm within the research community," said Kenneth Olden, Ph.D., director of NIEHS, one of the National Institutes of Health (http://www.nih.gov) . "Because the mouse strains will be sequenced in parallel, inter-strain comparison will begin right away, and their entire genomes will be complete within the next two years."
Mouse strains slated for sequencing include: 129S1/SvImJ, A/J, AKR/J, BALB/cByJ, BTBR T+ tf/J, C3H/HeJ, CAST/EiJ, DBA/2J, FVB/NJ, MOLF/EiJ, KK/HlJ, NOD/LtJ, NZW/LacJ, PWD/PhJ, and WSB/EiJ. Since these strains will be sequenced in reference to C57BL/6J, this project will yield extensive DNA information on a total of 16 strains.
"Knowing the organization of the mouse genome is a key component to identifying which gene-environment interactions are linked to disease in humans," said Dr. William Schrader, Director of the Center. "We'll start by mapping the DNA of 15 strains of mice most often used by researchers to study susceptibility to specific diseases. Then we can determine which diseases develop because of exposure to factors in the environment."
Almost all human genes have counterparts in mice. By examining the environmental triggers of disease in genetically distinct mice, researchers can gain a better understanding of the relationship between genes and the environment in the development of disease in humans. Almost 200 human diseases are affected by exposure to environmental substances. For most diseases, more than one gene is involved and researchers must discover the complex interplay among genes in order to understand how diseases develop.
Examples of diseases targeted for study include: cancer, Parkinson's, Alzheimer's, asthma, and developmental disorders such as autism. Researchers already have identified dozens of genetic components to these disorders, but few well-established animal models are available for understanding the interplay of genes and environment. Therefore, in addition to conducting the Resequencing Project, the Center for Rodent Genetics will build a web-based storehouse of mouse research models accessible to scientists throughout the world.
"The data base will allow scientists to pin-point the models most useful for their own research and will allow them to focus their work on the more likely genetic links to disease," said Dr. Olden. "This will help us identify the causes of disease faster and will make research and drug development more cost effective."
The Resequencing Project, which will be conducted through a 2-year contract with Perlegen Sciences, Inc. of Mountain View, CA, is a foundational effort in a long-term plan. For the first five years, the Center for Rodent Genetics will foster efforts to investigate environmental exposures and disease susceptibility, identify disease mechanisms and pathways, compare mouse and human biomarkers, and encourage development of rapid cell-based methods for comparing the effects of environmental exposures. By the third year, the Center will begin translating research findings to population analysis and to toxicology testing. These studies will also influence the development of curative treatment and regulatory decisions.
"Before genetic mapping, we were able to expose a mouse to environmental toxins and see 'if' a disease developed, but with genetic information, we can also understand 'why' a disease develops," said Olden. "Technology is accelerating both toxicology and environmental health research. NIEHS will lead the way in these two disciplines to make predictions about disease."
The Center for Rodent Genetics will compile the results of genetic research on mice being conducted by several divisions within NIEHS. It also will align with other research initiatives within the National Institutes of Health that use genetically-modified organisms.
"We are not carrying out this work alone. We're coordinating our work to complement other projects, especially the Human Genome Project, which is where we expect to see the most return on our investment," said Dr. Schrader.
The National Institute of Environmental Health Sciences supports research to understand the effects of the environment on human health.
Researchers Identify Brain Protein That Halts Progression of Alzheimer's
Researchers have identified a protein in the brain that halts the progression of Alzheimer's disease in human brain tissue. The protein, known as "transthyretin," protects brain cells from gradual deterioration by blocking another toxic protein that contributes to the disease process.
The (http://www.niehs.nih.gov), a component of the National Institutes of Health (http://www.nih.gov) , provided $1.25 million to University of Wisconsin-Madison scientists for the transthyretin study. The scientists will present their findings October 26 at the 34th annual meeting of the Society for Neuroscience in San Diego, Calif.
"The results of this study are promising," said Kenneth Olden, Ph.D., director of the NIEHS. "More studies are needed to understand how transthyretin can be used in treating Alzheimer's patients."
Alzheimer's disease progresses when a toxic protein, known as "beta-amyloid," attacks the brain's nerve cells involved in learning and memory. The beta-amyloid creates sticky plaques and tangles that gradually disable nerve cells, producing memory loss. Transthyretin appears to protect brain cells by intercepting the beta-amyloid and preventing it from interacting with the brain tissue.
"Based on the results of animal studies, we know that the disease process depends in large part on the delicate balance between the 'good' transthyretin protein and the 'bad' beta-amyloid protein," says Dr. Jeff Johnson, associate professor at the University of Wisconsin's School of Pharmacy and lead author on the study. "In Alzheimer's patients, the 'bad' proteins significantly outnumber the 'good' proteins."
Johnson discovered the effect of transthyretin while studying mice genetically engineered with defective genes taken from human patients with early-onset Alzheimer's disease. As expected, the defective genes produced mice with higher-than-normal levels of the toxic beta-amyloid protein. These mice did not, however, exhibit symptoms of Alzheimer's disease.
"We have a mouse whose brain is bathing in toxic beta-amyloid without exhibiting disease symptoms," says Johnson. "We were all asking the same question - Why aren't these nerve cells dying?"
Dr. Thor Stein, a researcher in Johnson's laboratory and first author of the study, then analyzed the brains of mice and noticed that the levels of transthyretin had increased dramatically. When Stein treated the mouse brain with an antibody that prevented transthyretin from reacting with the beta-amyloid protein, the mice showed brain cell death. "We concluded that the transthyretin must have protected the brain cells from the toxic effects of the beta-amyloid," says Johnson
Test tube studies with cultured brain cells from human cortex support the findings. When Stein treated human brain cells with the transthyretin protein, then exposed the cells to the toxic beta-amyloid, the brain cell death was minimal. "Now that we have demonstrated that this protective mechanism is relevant to humans, we can start to identify strategies to slow nerve degeneration in Alzheimer's patients," says Johnson.
According to Johnson, this would involve developing drugs that would boost the transthyretin within the brain or methods depositing transthyretin into the brain. "Hopefully this research will inspire a new approach to the treatment of Alzheimer's, one focused on preventing the loss of the brain cells instead of treating the resulting symptoms."
Johnson foresees a time when family members with a genetic predisposition to Alzheimer's disease could take a yet-undeveloped drug to increase transthyretin protein and prevent the disease from developing. Theoretically, the drug also could be given in the early stages of Alzheimer's to stop progression of the disease, preserving a higher level of cognitive function in patients.
The transthyretin discovery will likely impact the screening of environmental chemicals for their potential role in causing or exacerbating Alzheimer's disease. "Researchers could develop tests that determine whether a particular chemical or agent in the environment is able to shift the delicate balance between the 'good' and 'bad' proteins," notes Johnson. "This would allow scientists to establish definitive links between environmental exposures and Alzheimer's disease pathology."
Pediatricians Need More Training on Environmental Health