EDITOR'S PICK: I-1c gene therapy: not such a good idea in heart failure?
Several lines of evidence, including the observation that the protein I-1 is downregulated in human failing hearts, have led to the suggestion that gene therapy to express a constitutively active form of the protein (I-1c) might provide a new approach to treating heart failure. However, Ali El-Armouche, Thomas Eschenhagen, and colleagues, at University Medical Center Hamburg-Eppendorf, Germany, have now generated data in mice indicating that I-1c might have deleterious effects on the heart under certain circumstances, leading them to suggest that the benefit/risk ratio of I-1c gene therapy should be reevaluated.
In the study, I-1–deficient mice were engineered to express I-1c in heart muscle cells (dTGI-1c mice). The hearts of young, resting dTGI-1c mice showed enhanced contractile function. However, when the mice were infused with catecholamine, a hormone released by the body in response to stress, they developed abnormal heartbeats and were susceptible to sudden death. Furthermore, the hearts of aged dTGI-1c mice were found to spontaneously develop the characteristic features of heart failure. As heart failure tends to be a disease of the elderly, the authors suggest that their data need to be considered by those developing I-1c gene therapy for the treatment of heart failure.
TITLE: Constitutively active phosphatase inhibitor-1 improves cardiac contractility in young mice but is deleterious after catecholaminergic stress and with aging
University Medical Center Göttingen, Göttingen, Germany.
Phone: 49-551-39-22602; Fax: 49-551-5699; E-mail: email@example.com
University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Phone: 49-40-7410-52180; Fax: 49-40-7410-54876; E-mail: firstname.lastname@example.org.
View this article at: http://www.jci.org/articles/view/40545?key=6aaaec79fcaa30d87e28
EDITOR'S PICK: Why certain anticancer drugs can cause heart failure in some patients
Several types of cancer are characterized by overexpression of PDGFR proteins, and molecules that inhibit PDGFR signaling have proven useful anticancer therapeutics. Recently, however, several such anticancer drugs have been associated with clinical heart failure in some patients. Aarif Khakoo and colleagues, at the University of Texas MD Anderson Cancer Center, Houston, have now identified a role for PDGFR-beta in mouse heart muscle cells that might help explain why inhibitors of PDGFR signaling can cause heart failure.
In the study, expression and activation of PDGFR-beta was found to increase dramatically in the hearts of mice exposed to pressure overload (a model of high blood pressure). Further, mice lacking PDGFR-beta in heart muscle cells developed more severe heart failure when exposed to pressure overload than did normal mice. Further analysis indicated that PDGFR-beta in heart muscle cells contributes to the protective response to pressure overload by triggering the growth of new blood vessels, providing new insight into the physiologic functions of PDGFR-beta.
TITLE: Cardiomyocyte PDGFR-beta signaling is an essential component of the mouse cardiac response to load-induced stress
Aarif Y. Khakoo
University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Phone: (713) 563-3563; Fax: (713) 563-0462; E-mail: email@example.com.
View this article at: http://www.jci.org/articles/view/39434?key=9ac310c34a9a682962db
NEUROBIOLOGY: Learning from a faithful model of inherited stroke
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the name given to the most common inherited form of stroke and vascular dementia. Although it is known to be caused by mutations in the gene NOTCH3, how these mutations lead to disease has not been determined, largely because there is no good animal model of the disease. However, a team of researchers, at Inserm U740, Université Paris 7-Denis Diderot, France and the Max-Delbruck-Center for Molecular Medicine, Germany, has now generated a mouse model of CADASIL and used it to identify very early events triggered by a CADASIL-causing mutant Notch3 that ultimately lead to key features of CADASIL-like disease.
The team, led by Anne Joutel and Norbert Hubner, used a large P1-derived artificial chromosome to overexpress in mice a large genomic segment containing a CADASIL-causing Notch3 mutation in a manner consistent with normal Notch3 expression. Initial analysis determined that the mice developed the hallmarks of CADASIL. Further analysis uncovered evidence that dysfunction in blood vessels in the brain and failure of the microcirculation are very early events triggered by the CADASIL-causing mutant Notch3 that ultimately lead to key features of the CADASIL-like disease. The authors hope that additional studies using these mice will identify other disease-causing mechanisms and provide insight into potential treatments for CADASIL.
TITLE: Cerebrovascular dysfunction and microcirculation rarefaction precede white matter lesions in a mouse genetic model of cerebral ischemic small vessel disease
Inserm U740, Université Paris 7-Denis Diderot, Paris, France.
Phone: 331-5727-8593; Fax: 331-5727-8594; E-mail: firstname.lastname@example.org.
Max-Delbruck-Center for Molecular Medicine, Berlin, Germany.
Phone: 4930-9406-3512; Fax: 4930-9406-3147; E-mail: email@example.com.
View this article at: http://www.jci.org/articles/view/39733?key=e6e3303d9710351a5db3
ONCOLOGY: The protein Brachyury promotes tumor spreading
Tumors often spread from their initial site of discovery (a process known as metastasis). Most deaths from cancer are caused by metastatic tumors, not the original ones. Many researchers are therefore seeking to understand the molecules involved in metastasis in the hope that they might provide new anticancer drug targets. A team of researchers, led by Jeffrey Schlom, at the National Institutes of Health, Bethesda, has now determined that the protein Brachyury induces tumor cells to undergo a process known as epithelial-mesenchymal transition, which is important for tumors to spread from their original site. As inhibition of Brachyury reduced the ability of human tumor cells to metastasize to the lung after transplantation into mice, the authors suggest that Brachyury may be an attractive drug target for anticancer therapeutics.
TITLE: The T-box transcription factor Brachyury promotes epithelial-mesenchymal transition in human tumor cells
National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Phone: (301) 496-4343; Fax: (301) 496-2756; E-mail: firstname.lastname@example.org.
View this article at: http://www.jci.org/articles/view/38379?key=f0aae258001b203e276e
DERMATOLOGY: The protein N-WASP helps hair growth
Various human skin disorders are associated with aberrant regulation of the cytoskeleton (the scaffolding that supports the cell). This is because many physiological processes in the skin, including wound healing and hair follicle cycling, involve cytoskeleton reorganization regulated by the proteins Cdc42 and Rac1. A team of researchers, led by Scott Snapper, at Massachusetts General Hospital, Boston, has now determined that the protein N-WASP, which acts downstream of Cdc42 to regulate cytoskeleton reorganization, has a key role in skin function and hair follicle cycling by generating and analyzing mice lacking N-WASP in skin.
Analysis of the mice indicated that N-WASP is critical for cells of the outer layer of the skin to proliferate and for hair growth but is dispensable for wound healing. The role of N-WASP in hair growth was found to be a result of its key role in hair follicle cycling and in the maintenance and differentiation of hair follicle progenitor cells. As further analysis indicated that N-WASP regulated the function of the gene regulatory protein β-catenin in cells of the outer layer of the skin from hair follicles, the authors suggest that N-WASP promotes β-catenin–dependent gene expression, thereby supporting the differentiation of hair follicle progenitor cells.
TITLE: Neural Wiskott-Aldrich syndrome protein modulates Wnt signaling and is required for hair follicle cycling in mice
Scott B. Snapper
Massachusetts General Hospital, Boston, Massachusetts, USA.
Phone: (617) 724-8809; Fax: (617) 643-0195; E-mail: email@example.com.
View this article at: http://www.jci.org/articles/view/36478?key=5baa25f7708df3b2ed8c
METABOLIC DISEASE: Controlling the activity of the protein SIRT1 in the liver
The protein SIRT1 is a key regulator of many cell functions, including energy generation. A team of researchers, at the Mayo Clinic College of Medicine, Rochester, has now determined that the protein DBC1 regulates SIRT1 activity in the liver of mice.
The team, led by Eduardo Nunes Chini and Zhenkun Lou, found that when mice were fed a high-fat diet, SIRT1 activity decreased in the liver and this was associated with increased interaction with DBC1. By contrast, after 24 hours starvation, SIRT1 activity increased in the liver and this was associated with decreased interaction with DBC1. Consistent with these data, mice lacking DBC1 had higher than normal levels of SIRT1 activity in the liver and were protected from liver damage known as steatosis caused by eating a high-fat diet. The authors therefore propose that modulating DBC1-SIRT1 interactions might provide a way to treat liver steatosis caused by eating a high-fat diet.
TITLE: Deleted in breast cancer regulates SIRT1 activity and contributes to high-fat diet–induced liver steatosis in mice
Eduardo Nunes Chini
Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
Phone: (507) 255-0992; Fax: (507) 255-7300; E-mail: firstname.lastname@example.org.
Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
Phone: (507) 284-2702; Fax: (507) 393-0107; E-mail: email@example.com.
View this article at: http://www.jci.org/articles/view/39319?key=d34e7e5ea22ce9a7ecb8
ONCOLOGY: The protein beta-catenin distinguishes regeneration from formation of cancer precursor lesions
As pancreatic ductal adenocarcinoma (PDA) is the fourth leading cause of cancer death in the United States, researchers are keen to understand what signaling pathways control pancreatic cell function and maintenance. Cells lining the ducts of the mouse pancreas known as acinar cells respond to injury that mimics acute pancreatitis by either regenerating or forming PDA precursor lesions. A team of researchers, led by Matthias Hebrok, at the University of California at San Francisco, San Francisco, has now identified a signaling pathway in mice that dictates whether acinar cells respond to injury that mimics acute pancreatitis by regenerating or forming PDA precursor lesions. Specifically, they determined that signaling via the protein beta-catenin is required for efficient acinar regeneration in mice and that this signaling does not occur when PDA precursor lesions form as a result of expression of the cancer-promoting protein Kras.
TITLE: Beta-catenin blocks Kras-dependent reprogramming of acini into pancreatic cancer precursor lesions in mice
The University of California at San Francisco, San Francisco, California, USA.
Phone: (415) 514-0820; Fax: (415) 564-5813: E-mail: firstname.lastname@example.org.
View this article at: http://www.jci.org/articles/view/40045?key=25f9f71addc1afc3f1aa
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