JCI table of contents: December 1, 2006

December 01, 2006

EDITOR'S PICK: Silencing the cause of mad cow disease

BSE (more commonly known as mad cow disease) and CJD, which is a related disease in humans that can occur spontaneously, be inherited, or be acquired (in some cases probably from cows with BSE), are fatal neurodegenerative diseases. It is thought that these diseases are caused by accumulation in the brain of an abnormally folded version (PrPsc) of a natural protein (PrPc). There are currently no therapies for the treatment of these diseases, making this an area of active investigation.

In a study appearing in the December issue of the Journal of Clinical Investigation, Alexander Pfeifer and colleagues from the University of Bonn, Germany, show that in mice silencing of the gene encoding PrPc suppresses the accumulation of PrPsc. In vitro, silencing the gene encoding PrPc, using a technique known as RNA interference (RNAi), in already diseased neurons suppressed the accumulation of PrPsc. Similarly, in mice engineered to express the gene silencing therapeutic in a varying proportion of their neurons, the accumulation of PrPsc was markedly delayed, with the delay in accumulation of PrPsc being directly correlated with the proportion of neurons in the brain expressing the gene silencing therapeutic. This study therefore provides hope that RNAi might provide a new approach for the development of a therapeutic to treat individuals and animals with neurodegenerative disorders such as CJD and BSE. However, as Qingzhong Kong from Case Western Reserve University says in an accompanying commentary "Much more research is needed before RNAi can be harnessed to treat..." these neurodegenerative disorders.

TITLE: Lentivector-mediated RNAi efficiently suppresses prion protein and prolongs survival of scrapie-infected mice

AUTHOR CONTACT:
Alexander Pfeifer,
University of Bonn, Bonn, Germany.
Phone: +49-228-735410; Fax: +49-228-735404; E-mail: alexander.pfeifer@uni-bonn.de.

Hans Kretzschmar
University of Munich, Munich, Germany.
Phone: +49-89-2180-78001; Fax: +49-89-2180-78037; Email: hans.kretzschmar@med.uni-muenchen.de.

View the PDF of this article at: https://www.the-jci.org/article.php?id=29236

ACCOMPANYING COMMENTARY

TITLE: RNAi: a novel strategy for the treatment of prion diseases

AUTHOR CONTACT:
Qingzhong Kong
Case Western Reserve University, Cleveland, Ohio, USA.
Phone: (216) 368-1756; Fax: (216) 368-2546; E-mail: qxk2@case.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=30663




EDITOR'S PICK: Immune responses spread from one protein to another in type 1 diabetes

Type 1 diabetes (T1D) is caused by the immune system inappropriately attacking the cells in the pancreas that produce insulin, the hormone that controls blood sugar levels. Although many of the proteins attacked by the immune system during T1D have been identified, it has not been determined whether immune responses to the individual proteins develop independently or whether a response to just one protein then spreads to other proteins. But now, in a study appearing in the December issue of the Journal of Clinical Investigation, researchers from St. Vincent's Institute, Australia, have shown that in a mouse model of T1D the immune system first attacks a single protein, known as proinsulin, and then expands its attack to other proteins.

Using mice that develop a disease very similar to T1D (NOD mice), Thomas Kay and colleagues showed that NOD mice that were unable to mount an immune response to proinsulin also had no immune cells that recognized a second protein IGRP and did not develop diabetes. By contrast, NOD mice that were unable to mount an immune response to IGRP had immune cells that recognize proinsulin and developed diabetes. This study demonstrates that diabetes in NOD mice is triggered by an immune response to a single protein that then spreads to other proteins. This study therefore has important implications for the development of therapeutics designed to make individuals with T1D no longer mount an immune response to a particular protein.

In an accompanying commentary, Lucienne Chatenoud and Sylvaine You from the Hôpital Necker-Enfants Malades, France, discuss how it is important to determine the molecular and cellular events that underlie this spreading of the immune response so that the information can be translated to therapeutics for T1D and perhaps other autoimmune diseases.

TITLE: Responses against islet antigens in NOD mice are prevented by tolerance to proinsulin but not IGRP

AUTHOR CONTACT:
Thomas W. H. Kay
St. Vincent's Institute, Fitzroy, Victoria, Australia.
Phone: +61-3-9288-2480; Fax: +61-3-9416-2676; E-mail: tkay@svi.edu.au.

View the PDF of this article at: https://www.the-jci.org/article.php?id=29602

ACCOMPANYING COMMENTARY

TITLE: Proinsulin: a unique autoantigen triggering autoimmune diabetes

AUTHOR CONTACT:
Lucienne Chatenoud
Hôpital Necker-Enfants Malades, Paris, France.
Phone: +33-144-49-53-73; Fax: +33-143-06-23-88; E-mail: chatenoud@necker.fr.

View the PDF of this article at: https://www.the-jci.org/article.php?id=30760




METABOLIC DISEASE: Fat tissue gains weight from the bone marrow

As individuals become obese their adipose tissue (fat tissue) increases in mass. This is because individual cells in the adipose tissues (adipocyte) increase in size and because an increased number of adipocytes are generated. It had been thought that new adipocytes were only generated from precursors already present in adipose tissue. But now, in a study appearing in the December issue of the Journal of Clinical Investigation, researchers from the University of Colorado Health Sciences Center show that in mice, adipocytes can be generated from progenitor cells originating in the bone marrow.

Dwight Klemm and colleagues transplanted mice with bone marrow marked with a fluorescent protein and found that when these mice were treated with the drug rosiglitazone (which is used to treat individuals with type 2 diabetes) adipocytes expressing the fluorescent marker could be detected in the adipose tissue. Feeding the transplanted mice with a high-fat diet had a similar effect. Treatment with rosiglitazone also caused an increase in the number of mesenchymal and hematopoietic progenitors in the blood system, leading the authors to suggest that these progenitors might be the precursors of the new adipocytes.

In an accompanying commentary, Gary Hausman and Dorothy Hausman discuss how this work provides an unexpected avenue of research for the field of adipocyte biology and for understanding the changes that occur as individuals become obese.

TITLE: Rosiglitazone promotes development of a novel adipocyte population from bone marrow-derived circulating progenitor cells

AUTHOR CONTACT:
Dwight J. Klemm
University of Colorado Health Sciences Center, Denver, Colorado, USA.
Phone: (303) 315-8107; Fax: (303) 315-4871; E-mail: Dwight.Klemm@UCHSC.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=28510

ACCOMPANYING COMMENTARY

TITLE: Search for the preadipocyte progenitor cell

AUTHOR CONTACT:
Gary J. Hausman
United States Department of Agriculture -- Agricultural Research Service, Athens, Georgia, USA.
Phone: (706) 583-8275; Fax: (706) 542-0399; E-mail: ghausman@saa.ars.usda.gov.

View the PDF of this article at: https://www.the-jci.org/article.php?id=30666




PULMONARY: Platelets key to acute lung injury

Acute lung injury (ALI) is a relatively common life-threatening condition that can be caused by sepsis, trauma, and acid aspiration, which can be a complication of general anesthesia. Currently there are no good therapies for the treatment of ALI, but a study appearing in the December issue of the Journal of Clinical Investigation has identified new potential therapeutic targets for the treatment of individuals with ALI.

Klaus Ley and colleagues from the University of Virgina show that platelet-neutrophil interactions have a key role in the development of disease in a mouse model of acid aspiration-induced ALI. Reducing the number of platelets in the mice or inhibiting the platelet-neutrophil interaction reduced the recruitment of neutrophils to the lungs, reduced lung permeability, improved gas exchange in the lungs, and prolonged survival. Mechanistically, expression of a molecule known as P-selectin by the platelets was crucial for mediating the platelet-neutrophil interaction, which induced platelets to produce proinflammatory factors such as TXA2. The authors therefore suggest that disrupting the platelet-neutrophil interaction or blocking the proinflammatory factors produced as a result of this interaction might provide new therapeutic targets for the treatment of individuals with ALI.

In an accompanying commentary, Wolfgang Kuebler suggests that although this study highlights the importance of platelets in ALI, they might also have an important role in the development of other "...lung inflammatory disorders, including asthma, chronic obstructive pulmonary disease, and cystic fibrosis."

TITLE: Complete reversal of acid-induced acute lung injury by blocking of platelet-neutrophil aggregation

AUTHOR CONTACT:
Klaus Ley
University of Virginia, Charlottesville, Virginia, USA.
Phone: (434) 243-9966; Fax: (434) 924-2828; E-mail: klausley@virginia.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=29499

ACCOMPANYING COMMENTARY

TITLE: Selectins revisited: the emerging role of platelets in inflammatory lung disease

AUTHOR CONTACT:
Wolfgang M. Kuebler
Charité Universitaetsmedizin Berlin, Berlin, Germany.
Phone: +49-0-30-8445-1648; Fax: +49-0-30-8445-1634; E-mail: wolfgang.kuebler@charite.de.

View the PDF of this article at: https://www.the-jci.org/article.php?id=30664




VASCULAR BIOLOGY: Megakaryocytes and platelets keep blood vessel growth under control

The growth of new blood vessels (a process known as angiogenesis) is essential during embryonic development, wound healing, and blood cell development in the bone marrow, but it also has a role in supporting tumor growth. It is a finely tuned process regulated by a balance of pro- and anti-angiogenic factors, and in a study appearing in the December issue of the Journal of Clinical Investigation, researchers from Weill Medical College, New York, show that in mice, two types of blood cell (known as megakaryocytes and platelets) produce antiangiogenic factors known as thrombospondins.

Using mice lacking both thrombospondin 1 and thrombospondin 2, Shahin Rafii and colleagues showed that the production of these factors limits the angiogenesis that supports blood cell development in the bone marrow after treatment with chemotherapeutic drugs. These factors also limited the blood vessel growth that accompanies wound healing in response to a loss of blood flow in the tissues. The increased blood vessel growth in these situations was mediated by increased activation of a protein known as MMP9 and by increased production of a proangiogenic factor known as SDF1. This study has clinical implications because inhibiting the release of thromobospondins by megakaryocytes and platelets might provide a new approach to enhance blood vessel growth (and thereby restore blood cell development) after chemotherapy.

In an accompanying commentary, Judith Varner, from the Moores UCSD (University of California, San Diego) Cancer Center, discusses how the identification of these antiangiogenic factors furthers our understanding of the finely regulated process of angiogenesis, and highlights some of the questions that remain to be answered.

TITLE: Thrombospondins deployed by thrombopoietic cells determine angiogenic switch and extent of revascularization

AUTHOR CONTACT:
Shahin Rafii
Weill Medical College of Cornell University, New York, New York, USA.
Phone: (212) 746-2070: Fax: (212) 746-8481; E-mail: srafii@med.cornell.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=29314

ACCOMPANYING COMMENTARY

TITLE: The sticky truth about angiogenesis and thrombospondins

AUTHOR CONTACT:
Judith A. Varner
Moores UCSD Cancer Center, La Jolla, California, USA.
Phone: (858) 822-0086; Fax: (858) 822-1325; Email: jvarner@ucsd.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=30685




PULMONARY: Immune cells get together in the lung of patients with rheumatoid arthritis

Cells of the immune system congregate at various sites throughout the body, and it is at these sites that they become primed to respond to invading microbes. Although in some species immune cell congregates can be found in the airways of the lung at all times, most healthy humans lack these congregates (which in the lung are known as bronchus-associated lymphoid tissues (BALT). Now, in a study appearing in the December issue of the Journal of Clinical Investigation, Troy Randall and colleagues from the Trudeau Institute have shown that BALT is induced to form in the airways of the lungs of patients with various lung diseases. In particular, inducible BALT was observed in rheumatoid arthritis (RA) patients with pulmonary complications. The inducible BALT was most developed in individuals with high levels of expression of molecules involved in the pathogenesis of RA and its presence correlated with tissue damage in the lungs. This study leads the authors to suggest that inducible BALT might have a role in the lung pathogenesis associated with RA and that understanding the mechanisms by which BALT is induced in the airways of the lung might provide new targets for the treatment of this disease.

TITLE: Inducible bronchus-associated lymphoid tissue (iBALT) in patients with pulmonary complications of rheumatoid arthritis

AUTHOR CONTACT:
Troy D. Randall
Trudeau Institute, Lake Saranac, New York, USA.
Phone: (518) 891-3080; Fax: (518) 891-5126; E-mail: trandall@trudeauinstitute.org.

View the PDF of this article at: https://www.the-jci.org/article.php?id=28756




METABOLIC DISEASE: PDE3B regulates energy levels in mice

Insulin acts on many cells to exert its control over the amount of energy that is available to the body. When cells become resistant to the effects of insulin, type 2 diabetes and other metabolic disorders can develop. Understanding the molecular pathways by which insulin affects the different cells might provide clues as to why insulin resistance develops. Now, in a study appearing in the December issue of the Journal of Clinical Investigation, researchers from the National Heart, Lung and Blood Institute have shown that a protein known as PDE3B has a non-redundant role in some of the molecular pathways activated by insulin in mice.

Young Hun Choi and colleagues generated mice lacking PDE3B and found that lipid metabolism, which is regulated by insulin, was dysregulated in these animals. Although when stimulated, PDE3B-deficient mice secreted more insulin than normal mice, the PDE3B-deficient mice were less able to control their blood glucose levels and to regulate lipid metabolism. This demonstration of insulin resistance in PDE3B-deficient mice indicates that PDE3B has an irreplaceable role in the molecular pathways that are activated by insulin. The authors therefore suggest that altered expression or activity of PDE3B might have a role in the development of insulin resistance in humans.

TITLE: Alterations in regulation of energy homeostasis in cyclic nucleotide phosphodiesterase 3B-null mice.

AUTHOR CONTACT:
Young Hun Choi
National Institutes of Health, Bethesda, Maryland, USA.
Phone: (301) 402-4774; Fax: (301) 402-1610; E-mail: Choiy@nhlbi.nih.gov.

View the PDF of this article at: https://www.the-jci.org/article.php?id=24867
-end-


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