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RESEARCH HIGHLIGHTS:
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5/1/06
Eat Less, Weigh More? Enzyme Makes Lean Mice Less Susceptible to Dietary Fat
Working with genetically engineered mice, Hopkins scientists have interfered with the brain’s ability to control an animal’s response to a high-fat diet. The report, published in Proceedings of the National Academy of Sciences, is based on the identification of a gene – CPT1c – used in the brain to manage body weight.
The newly discovered gene makes a protein found only in the brain, notably in the region that controls hunger, thirst and metabolism – the hypothalamus. Proteins similar to CPT1c are known to help break down fat to release energy to feed cells. Mice lacking the CPT1c gene are the same length as their littermates who carry normal copies of the gene but on average weigh 15 percent less when fed a low-fat diet.
Further analysis revealed that when deprived of food for four hours prior to feeding with standard laboratory mouse chow, the knockout mutant mice ate about 25 percent less food than their normal siblings. Therefore, the researchers concluded, CPT1c must play a role in feeding behavior and appetite control. When fed a high-fat diet (mouse chow laced with lard) for 10 weeks, mice lacking CPT1c still ate less than their normal littermates, but they were much heavier.
Previously, the same researchers showed that a molecule called malonyl-CoA is critical for fat metabolism. And as it turns out, malonyl-CoA interacts with CPT1c, according to Lane. Increasing the amount of malonyl-CoA in the liver causes those cells to make and store fat. Increasing malonyl-CoA in the hypothalamus somehow tells the cells in the body to break down fats for energy and the muscle cells to use more energy. Therefore, identifying molecules that interact with malonyl-CoA will help scientists understand how energy balance and body weight is controlled. http://www.hopkinsmedicine.org/Press_releases/2006/05_01_06.HTML
PNAS, May 9, 2006 vol. 103 no. 19:7282-7287
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5/8/06
Bedsores and Bald Hides: Novel Roles Revealed For A “Scaffolding” Protein
A protein long thought to provide only mechanical support for keeping cells and tissues from literally falling apart turns out to have much wider utility. In a pair of reports, the protein K17 has been found to also influence wound healing and maintain the structural integrity of hair follicles, according to Johns Hopkins researchers.
The wound-healing work, published in Nature, sheds light on how the body repairs wounds and may have implications for preventing or treating chronic wounds such as pressure or bed sores arising from long periods of immobility. Along with the pain and scarring, bed sores significantly increase health care costs in nursing homes and hospitals.
A separate report by the same Hopkins group, published in Genes and Development, reports a new and different role for the same protein in promoting hair follicle growth, although the investigators were quick to caution that there’s nothing in their work – yet – to suggest a way to prevent or cure human baldness.
K17 belongs to a family of proteins known as keratin intermediate filaments, which are part of the cytoskeleton, an intricate network of flexible protein fibers that maintain cell shape and strength. By studying mice genetically engineered to lack K17, the Hopkins researchers discovered that cells need it to turn on signals that lead to the manufacture of new proteins and cell growth when skin is damaged.
“Here we show an entirely novel and possibly independent, nonmechanical function in which these filaments latch onto and regulate cell signaling proteins,” says the study’s senior author, Pierre A. Coulombe, Ph.D., professor of biological chemistry in the Institute for Basic Biomedical Sciences at Hopkins. “The involvement of K17 in wound healing has not previously been known to influence the making of proteins, and this information has profound implications for our understanding of the role of the cytoskeleton in damaged cells,” Coulombe says. http://www.hopkinsmedicine.org/Press_releases/2006/05_17a_06.html
Nature 441, 362-365 18 May 2006
Genes & Development 20:1353-1364, 2006
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5/11/06
How Bad is Malarial Anemia? It May Depend On Your Genes
Cell and animal studies conducted jointly by scientists at Johns Hopkins, Yale and other institutions have uncovered at least one important contributor to the severe anemia that kills almost half of the 2 million people worldwide who die each year of malaria. The culprit is a protein cells make in response to inflammation called MIF, which appears to suppress red blood cell production in people whose red blood cells already are infected by malaria parasites.
The study, published online April 24 in the Journal of Experimental Medicine, adds to a growing amount of evidence that an individual’s unique genetic makeup can affect the prevalence and outcome of diseases, in this case the individual risk of malarial anemia.
A number of human proteins, including MIF (which stands for migration inhibitory factor), were long suspected to cause malarial anemia because they are known to reduce red blood cell counts as part of the body’s normal response to such inflammatory conditions as rheumatoid arthritis or some cancers.
Using immature blood cell precursors grown in a dish, the research team showed that adding MIF to the cells decreases both the final number and maturity of red blood cells. The researchers believe this effect can lead to anemia.
When infected with plasmodium, mice genetically engineered to lack MIF experience less severe anemia and are more likely to survive. Without MIF around to prevent blood cells from maturing, the mice appear better able to maintain their oxygen carrying capacity and don’t lose as much hemoglobin, the protein found in red blood cells responsible for binding to oxygen molecules. http://www.hopkinsmedicine.org/Press_releases/2006/05_11_06.html
Journal of Experimental Medicine, published online April 24
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5/23/06
Robotic Joystick Reveals How Brain Controls Movement
By training a group of human subjects to operate a robot-controlled joystick, Johns Hopkins researchers have shown that the slower the brain “learns” to control certain muscle movements, the more likely it is to remember the lesson over the long haul. The results, the investigators say, could alter rehabilitation approaches for people who have lost motor abilities to brain injuries like strokes.
In a report on the work published May 23 in PLoS Biology, the researchers built on their observations that some parts of the brain learn – and forget – fast, while others learn more slowly and more lastingly. Both types of learning are critical.
Neuroscientists long have thought that two things are required for mastering such muscle control – time and error. Time refers to the need to “sleep on it,” for the brain to somehow process and “remember” how to carefully control muscles.
To test the need for time in mastering muscle control, the research team designed a simple and short task. Fourteen healthy human subjects were asked to hold onto a robot-controlled joystick and keep it from moving as the robot driver pushed repeatedly – in quick pulses – to one side. The joystick then pushed repeatedly in the opposite direction and again the subjects were asked to keep the joystick centered.
The robot-controlled joystick used in these experiments can measure precisely how hard and in what direction it’s being pushed by the hand holding it. Using computer programs, the researchers then were able to apply mathematical equations to these measurements and calculate predictions of how the brain might be “learning” these simple movements.
First, the computer programs were able to tease out that the brain picked up the control task quickly, but actually forgot the task quickly as well. But, at the same time, the brain also was learning the same task more slowly, and that was responsible for the subjects’ being able to “remember” the initial joystick-pushing movement.
“Rehab is about training, and you want to be able to train the slow-learning system to be successful,” says the report’s senior author, Reza Shadmehr, Ph.D., a professor of biomedical engineering in the Institute of Basic Biomedical Sciences at Hopkins. http://www.hopkinsmedicine.org/Press_releases/2006/05_23_06.html
PLoS Biology Volume 4, Issue 6, June 2006
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NEWS BRIEFS:
NeuroICE Members Awarded and Recognized
Hongjun Song, Ph.D., an assistant professor of neurology in the Johns Hopkins Institute for Cell Engineering Program for Neuroregeneration and Repair – known as NeuroICE –has been awarded the McKnight Scholar Award by the McKnight Endowment Fund for Neuroscience. Song studies the cellular and molecular mechanisms behind stem cells’ ability to self-renew. In particular, Song and his colleagues study the behavior of adult nerve stem cells and how those cells become nerves. The award provides $75,000 in funding each year for the next three years.
Three members of NeuroICE have received awards from the American Heart Association: Zhikai Chi, an M.D., Ph.D. candidate in the Dawson lab has received a predoctoral award for his work studying a new gene that may protect neurons from dying when the brain loses blood supply after injuries such as stroke; Shaoyo Ge, Ph.D., a research fellow in the Song lab, received a postdoctoral award; and Shaida Andrabi, M.Sc., Ph.D., a research fellow in the Dawson lab, received a postdoctoral award. Andrabi also won the “The Best Oral Presentation Award by a Student or Postdoctoral Fellow” for the presentation, “The role of poly-(ADP-ribose) polymer in neuronal cell death” at the 2006 East Coast PARP conference held May 18-20 in Quebec City, Canada.
Ted Dawson, M.D., Ph.D. and Valina Dawson, Ph.D. both were nominated to the Faculty of 1000 Biology in the section of neurobiology of disease and regeneration. Faculty of 1000 biology is an online literature service that evaluates and highlights the most noteworthy research papers, based on reviews by a select faculty of over 1600 of the world’s leading scientists, published in the biological sciences.
Ted Dawson, M.D., Ph.D. also was named chairman of the scientific advisory board of the Bachmann-Strauss Dystonia and Parkinson Foundation. As chair, Dawson will be responsible for directing the research program and funding of the Foundation.
Aravinda Chakravarti receives Henry J. Knott Directorship and Professorship of Medical Genetics
Aravinda Chakravarti, Ph.D. received the Henry J. Knott Directorship and Professorship of Medical Genetics at the Johns Hopkins Kimmel Cancer Center on May 22. Chakravarti, who has served as director of the Hopkins' McKusick-Nathans Institute for Genetic Medicine since 2000, is the first recipient of the named endowment. Henry J. Knott was a Baltimore-based developer and businessman.
Hopkins Researchers Study Blood Vessel Development
Researchers in the departments of cell biology and chemical and biomolecular engineering at Johns Hopkins have shown that cells called presumptive vascular smooth muscle cells – also known as pericytes – communicate with extracellular matrix to regulate the development of new blood vessels. The extracellular matrix is an intricate network of proteins and sugars that provides support to tissues, provides a surface on which cells crawl and plays a role in controlling where and how far cells move. The extracellular matrix communicates with cells using proteins on the cell’s surface. The researchers believe that a protein called alpha-4 beta-1 integrin, a protein normally found on the surface of pericytes, is required to help pericytes spread evenly along vessels during blood vessel development. Mice genetically engineered to lack alpha-4 beta-1 integrin have blood vessels that are much larger in diameter than normal. When studied in culture dishes, pericytes from these mutant mice crawl more slowly and appear directionally challenged. The study was published May 1 in Developmental Biology.
Developmental Biology, Volume 293, Issue 1, 1 May 2006, Pages 165-177
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-- JHM --
