Journal Of Clinical Investigation Online News Feb. 8, 2010
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NEPHROLOGY: New approach to treating the kidney disease Alport syndrome?
Alport syndrome is a progressive hereditary kidney disease with no definitive therapy. It is caused by mutations in any of the collagen IV genes (COL4A3, COL4A4, and COL4A5). Motoko Yanagita and colleagues, at Kyoto University Graduate School of Medicine, Japan, have now identified a role for the protein USAG-1 in the development of disease in mice that model Alport syndrome (Col4a3-/- mice). As deletion of Usag1 in Col4a3-/- mice led to substantial attenuation of disease progression, preservation of kidney function, and extension of life span, the authors suggest that inhibiting USAG-1 might be a promising therapeutic approach for the treatment of Alport syndrome.
TITLE: Loss of the BMP antagonist USAG-1 ameliorates disease in a mouse model of the progressive hereditary kidney disease Alport syndrome
AUTHOR CONTACT: Motoko Yanagita Kyoto University Graduate School of Medicine, Kyoto, Japan.
View this article at: http://www.jci.org/articles/view/39569?key=c3580c682d75b2b119bd
HEMATOLOGY: Role for the protein HIF-2-alpha in Chuvash polycythemia
Individuals with a condition known as Chuvash polycythemia, which is caused by a specific mutation in the protein VHL, have a greater proportion of their blood volume occupied by red blood cells than do healthy individuals. They also have pulmonary hypertension (i.e., increased blood pressure in the blood vessels that go to and from the lung) and increased respiratory rates, although the mechanistic basis for these symptoms has not been determined. Now, Celeste Simon and colleagues, at the University of Pennsylvania School of Medicine, Philadelphia, have identified a role for the protein HIF-2-alpha in the lung complications of Chuvash polycythemia by studying mice that model the condition. Of particular interest, HIF-2-alpha activity was found to be increased in lungs from mice that model Chuvash polycythemia. Further, as loss of one copy of the gene responsible for generating HIF-2-alpha in mice that model Chuvash polycythemia suppressed both the polycythemia and pulmonary hypertension, the authors suggest that inhibiting HIF-2-alpha might provide a new approach to treat Chuvash disease.
TITLE: The von Hippel-Lindau Chuvash mutation promotes pulmonary hypertension and fibrosis in mice
AUTHOR CONTACT: M. Celeste Simon University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
View this article at: http://www.jci.org/articles/view/36362?key=78a2f13d85364cc6f65c
ONCOLOGY: Rab25: a suppressor of tumor formation in intestines?
Colorectal adenocarcinoma accounts for the majority of cases of colorectal cancer. A series of genetic mutations in the cells lining the colon (intestinal epithelial cells) is thought to be the cause of colorectal adenocarcinoma. By studying mouse models of colon cancer and tissue from individuals with colorectal adenocarcinoma, James Goldenring and colleagues, at Vanderbilt University School of Medicine, Nashville, have now identified RAB25 as one gene that might be involved in the formation of colorectal adenocarcinomas.
Initial analysis indicated that expression of Rab25 was substantially decreased in human colon adenocarcinomas compared with normal colon and that lower Rab25 expression predicted shorter patient survival times. To follow up on these data, which suggested that Rab25 functions as a tumor suppressor (that is, a protein that when expressed at lower than normal levels due to mutation of the gene responsible for its generation fails to prevent tumors forming) in intestinal epithelial cells, the authors analyzed Rab25-deficient mice. Although these animals showed no gross abnormalities, when they were crossed with mice that model a hereditary syndrome that predisposes to colon cancer (ApcMin/+ mice), the Rab25-deficient ApcMin/+ mice developed increased numbers of intestinal polyps and colonic tumors compared with parental ApcMin/+ mice. Similar results were obtained in a second mouse model of colorectal adenocarcinoma, providing further confirmation of the probable tumor suppressor role of Rab25 in intestinal epithelial cells.
TITLE: Loss of Rab25 promotes the development of intestinal neoplasia in mice and is associated with human colorectal adenocarcinomas
AUTHOR CONTACT: James R. Goldenring Vanderbilt University School of Medicine, Nashville, TN, USA.
View this article at: http://www.jci.org/articles/view/40728?key=23ce364555ecb5bda924
IMMUNOLOGY: Complete chemokine profile of a cell
Chemokines are a large group of proteins whose predominant function is to direct cell migration. They regulate many physiological and pathophysiological processes, in particular in the immune system. Dirk Homann and colleagues, at University of Colorado Denver, Aurora, have now developed a simple method to efficiently identify all the chemokines produced by a single cell type, something that has not been possible before.
The method developed by Homann and colleagues is a flow cytometry-based assay that uses commercially available chemokine-specific antibodies to efficiently detect within cells 37 of 39 mouse chemokines. Using this technique, the author were able to delineate the complete chemokine profiles of two types of immune cell (NK cells and B cells) in response to major polyclonal stimuli and to assess the chemokine response of immune cells known as DCs to bacterial infection. Importantly, the authors were able to adapt the method to analyze chemokine expression in human cells, leading them to suggest that this method will help researchers understand the roles of chemokines in health and disease.
TITLE: Comprehensive assessment of chemokine expression profiles by flow cytometry
AUTHOR CONTACT: Dirk Homann University of Colorado Denver, Aurora, CO, USA.
View this article at: http://www.jci.org/articles/view/40645?key=3ba73571f42f82ed7858
Journal of Clinical Investigation
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