Gerald L. Andriole
Urologist combats prostatic diseases
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Gerald L. Andriole Urologist combats prostatic diseases |
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Protein linked to Alzheimer's to be studied
By Gila Z. Reckess Researchers in the School of Medicine have received a four-year, $1.3 million grant from the National Institute for General Medical Sciences to continue studying Notch, a protein critical for normal embryonic development. Notch abnormalities in adulthood can lead to conditions such as stroke and cancer. The team, led by Raphael Kopan, Ph.D., associate professor of medicine and of molecular biology and pharmacology, recently found another interesting clinical link: Some strategies for treating Alzheimer's disease may interfere with Notch and may thereby cause undesired complications. Notch belongs to a category of proteins that transmits a signal from the outside of a cell to the inside. These proteins are embedded in the cell membrane, with one end sticking outside the membrane and the other end reaching inside the cell. When a molecule outside the cell latches onto the protein, it triggers a change. In most cases, that change is communicated to other proteins, initiating a cascade of events that ultimately turns on a gene in the cell's nucleus, thereby indirectly affecting cell activity. Kopan and his colleagues, however, found that Notch communicates in a unique way -- it turns on genes directly. When a molecule latches onto the outer end of Notch, the inner end is broken off by a group of enzymes, one of which is called gamma-secretase. The detached segment then whizzes to the nucleus where it directly turns on target genes. The interaction between Notch and gamma-secretase has direct implications for the treatment of Alzheimer's disease. In addition to its relationship with Notch, gamma-secretase is partly responsible for plaque buildup in the brain characteristic of Alzheimer's disease. The most promising anti-Alzheimer's drugs under investigation aim to prevent plaque buildup by blocking this enzyme. But Kopan's team discovered that interfering with gamma-secretase could have potentially lethal affects because Notch activity also could be affected. This new grant will enable the team to further examine the relationship between Notch and gamma-secretase. The researchers also will explore how Notch influences embryonic development by studying two types of mice: those completely lacking Notch and those that have a specific Notch mutation that interferes only with the protein's ability to be modified by gamma-secretase. Both groups of animals die early in embryonic development, each with severely damaged blood and brain cells. But there is one important difference between the two groups: Development of the mesoderm -- the middle of three layers of embryonic tissue, which later gives rise to vertebrae, ribs, skeletal muscle and organs such as the kidneys -- is more affected in one group than in the other. Mesoderm development remains healthier in mice with the Notch mutation than in those that completely lack Notch. This may imply that Notch is involved in mesoderm development in a way that does not involve gamma-secretase. Kopan wants to unravel how Notch functions independent of gamma-secretase. His team hopes to uncover new strategies for the treatment of Alzheimer's disease and diseases caused by disruptions in Notch activity. |
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