JCI Table of contents August 1, 2005

07/21/05

EDITOR'S PICK
3 papers present fresh paths to ponder Akt1 in the heart

Akt is a molecule involved in many cellular functions, including growth, survival, and metabolism. Akt exists in three isoforms – Akt1, Akt2, and Akt3, which have a substantial degree of functional overlap. In the heart and vasculature, Akt may be protective against ischemia and it may enhance cardiac function after heart failure. But Akt may also have detrimental effects.

In our August 1 issue, the Journal of Clinical Investigation presents three research papers that explore Akt1 in the heart, plus an accompanying commentary. The first paper, by Anthony Rosenzweig and colleagues at Harvard, and the second paper by Kenneth Walsh and colleagues at Boston University, both provide new insights into how Akt1 can be maladaptive in the heart. Both studies use transgenic mice that overexpress active Akt1 to show that this causes cardiac dysfunction, including hypertrophy and fibrosis.

The third paper in this issue, by William Sessa and colleagues at Yale University, explores which Akt isoform is responsible for mediating adaptive angiogenesis seen in the heart after ischemia. The authors find that Akt1, but not Akt2 or Akt3 is responsible.

In an accompanying commentary that discusses all three papers, Brian O'Neill and E. Dale Abel write, "Three separate studies published in this issue of the JCI now provide important new insight into the central role of Akt1 in the regulation of angiogenesis and the maladaptive or deleterious consequences of chronic unregulated Akt activation in the heart." They proceed to discuss the implications of this data.

TITLE 1: Phosphoinositide 3-kinase rescues the detrimental effects of chronic Akt activation in the heart during ischemia/reperfusion injury

AUTHOR CONTACT 1:
Anthony Rosenzweig
Massachusetts General Hospital, Charlestown, MA USA
Phone: 617-726-8286; Fax: 617-724-7387; E-mail: arosenzweig@partners.org

View the PDF of this article at: https://www.the-jci.org/article.php?id=23073

TITLE 2: Disruption of coordinated cardiac hypertrophy and angiogenesis contributes to the transition to heart failure

AUTHOR CONTACT 2:
Kenneth Walsh
Boston University School of Medicine, Boston, MA USA
Phone: 617-414-2392; Fax: 617-414-2391; E-mail: kxwalsh@bu.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=24682

TITLE 3: Akt1/Protein Kinase B alpha is critical for ischemic and VEGF-mediated angiogenesis

AUTHOR CONTACT 3:
William Sessa
Yale University School of Medicine, New Haven, CT USA
Phone: 203-737-2291; E-mail: william.sessa@yale.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=24726

ACCOMPANYING COMMENTARY:

TITLE: Akt1 in the cardiovascular system: friend or foe?

AUTHOR CONTACT:

E. Dale Abel
University of Utah School of Medicine, Salt Lake City, UT USA
Phone: 801-585-0727; Fax: 801-585-0701; E-mail: dale.abel@hmbg.utah.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=25900

IMMUNOLOGY
Gene therapy puts SCID on the skids

Severe combined immunodefiency (SCID) is a group of genetic diseases that are almost always fatal in infancy. SCID can be treated with a stem cell transplant, but most patients do not have compatible donors. There has been limited success using gene therapy to treat SCID, but the procedure has been far from optimal, with serious side effects.

In a new study appearing on August 1 in The Journal of Clinical Investigation, Naomi Taylor and colleagues from the Institut de Genetique Moleculaire de Montpellier provide the first report of a successful in vivo transcriptionally-targeted gene therapy for this genetic disease.

The researchers show that, in ZAP-70-deficient SCID mice, the ZAP-70 gene of interest can be directly introduced into T lymphoid progenitor cells by intrathymic injection of a T cell-specific lentiviral vector, avoiding any ex vivo manipulation that usually results in functional problems. This results in the presence of gene-modified T cells in the periphery. In their model, introduction of ZAP-70 corrected the defect in thymocyte maturation and T cells in the periphery were functional and polyclonal.

This work is the first demonstration of an in vivo therapy allowing specific genetic modulation of mature T lymphocytes. This has important implications, not only for the treatment of SCID but also for the treatment of other infectious and acquired diseases implicating T lymphocytes.

In a related commentary, Ruth Seggewiss and Cynthia Dunbar write, "using lentiviral vectors and in situ gene transfer may represent a safer approach…avoiding factors potentially linked to leukemogenesis."

TITLE: In vivo correction of ZAP-70 immunodeficiency by intrathymic gene transfer

AUTHOR CONTACT:
Naomi Taylor
Institut de Genetique Moleculaire de Montpellier, Montpellier, France
Phone: 33-467-613-628; Fax: 33-467-040-231; E-mail: taylor@igmm.cnrs.fr

View the PDF of this article at: https://www.the-jci.org/article.php?id=23966

ACCOMPANYING COMMENTARY:

TITLE: A new direction for gene therapy: intrathymic T cell–specific lentiviral gene transfer

AUTHOR CONTACT:
Cynthia E. Dunbar
NIH, National Heart, Lung and Blood Institute, Bethesda, MD USA
Phone: 301-496-1434; Fax: 301-496-8396; E-mail: dunbarc@nhlbi.nih.gov

View the PDF of this article at: https://www.the-jci.org/article.php?id=26041

IMMUNOLOGY
Navigating Type I Diabetes with a now accurate epitope map

For many years, people have tried to determine the particular peptide epitopes of foreign or self-antigens that are presented by a particular MHC class II allele. Thus, scanning for predicted binding motifs, and using phage libraries, have been used in binding assays to identify those peptide epitopes which might be of functional importance in the immune response to foreign antigens and proteins, or the immune response to self antigens in autoimmunity. Unfortunately, despite a number of studies showing that not all of these predictions are borne out, many laboratories have persisted in this method of identifying peptide epitopes.

In a new study appearing on August 1 in The Journal of Clinical Investigation, Emil Unanue and colleagues from Harvard find that 2 molecules, which are the principal molecules which mediate susceptibility to type I diabetes in man (DQ 8) and in the NOD mouse (I-Ag7) have similar function and sequence specificity.

The authors show that when they simply elute from purified DQ8 or I-Ag7 molecules isolated from transfected cells, the peptide epitopes are different from those predicted by other methods. This is important because it shows that prediction is not adequate for determining peptide epitopes seen by immune T cells in various disease states.

In an accompanying commentary, Hidde Ploegh writes, "the comprehensive data set presented here by Suri and coworkers will allow others to navigate the territory of autoimmunity with an accurate map in hand."

TITLE: Natural peptides selected by diabetogenic DQ8 and murine I-Ag7 molecules show common sequence specificity

AUTHOR CONTACT:
Emil Unanue
Washington University School of Medicine, St. Louis, MO USA
Phone: 314-362-7440; Fax: 314-362-4096; E-mail: unanue@pathbox.wustl.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=25350

ACCOMPANYING COMMENTARY:

TITLE: A molecule's right to choose: how diabetogenic class II MHC products bind peptides

AUTHOR CONTACT:
Hidde Ploegh
Harvard Medical School, Boston, MA USA
Phone: 617-432-4776; Fax: 617-432-4775; E-mail: ploegh@hms.harvard.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=26018

IMMUNOLOGY
Why pollen makes you go AAHHH-CHOOO!!!

Pollen exposure can cause allergic airway inflammation. The role of antigenic pollen proteins in this allergy is well characterized, but the contribution of other constituents in pollen grains in this process is unknown.

In a new study appearing on August 1 in The Journal of Clinical Investigation, Sanjiv Sur and colleagues from University of Texas Medical Branch show that pollen grains and their extracts contain cell membrane-associated enzymes called NADPH oxidases. These pollen NADPH oxidases increase reactive oxygen species in the lung and other pro-inflammatory factors in the fluid lining the airways.

Removal of NADPH oxidase activity from the pollen inhibited allergic airway inflammation in sensitized mice. Thus, oxidative stress generated by pollen NADPH oxidases boosts pollen antigen induced allergic airway inflammation.

In an accompanying commentary, Darren Ritsick and J. David Lambeth write, "These findings suggest that inhibition of the pollen oxidase may provide a way to antagonize allergic inflammation at a very early step."

TITLE: ROS generated by pollen NADPH oxidase provide a signal that augments antigen-induced allergic airway inflammation.

AUTHOR CONTACT:
Sanjiv Sur
University of Texas Medical Branch, Galveston, TX USA
Phone: 409-772-8993; Fax: 409-772-5841; E-mail: sanjivsur@yahoo.com

View the PDF of this article at:https://www.the-jci.org/article.php?id=24422

ACCOMPANYING COMMENTARY:

TITLE: Spring brings breezes, wheezes, and pollen oxidases

AUTHOR CONTACT:
J. David Lambeth
Emory University Medical School, Atlanta, GA USA
Phone: 404-727-5875; Fax: 404-727-2738; E-mail: noxdoc@mac.com

View the PDF of this article at: https://www.the-jci.org/article.php?id=26023

METABOLIC DISEASE
New hemochromatosis mutants can't pump iron

Juvenile Hemochromatosis is a genetic metabolic disorder where excessive iron is absorbed, resulting in dangerously high levels of iron in vital organs. It is caused by a mutation in a gene called hemojuvelin (Hjv) on chromosome 1.

Now, two papers appearing on August 1 in The Journal of Clinical Investigation, present new mouse models of this disease and present data regarding the normal function Hjv. Both groups, one led by Nancy Andrews at Harvard and the other led by Silvia Arber at the University of Basel, disrupt the Hjv gene to create the mice.

The mice have increased iron deposition in the liver, heart, and pancreas but have decreased iron levels in macrophages. The mice are unable to transmit the iron signal in the liver.

In an accompanying commentary, Vaulont, et al write that these two studies, "have paved the way for rapid progress in the development of…drugs…for hereditary hemochromatosis, secondary hemosiderosis, and chronic inflammatory anemias – pathologies that affect millions of patients around the world."

TITLE 1: Hemojuvelin Is Essential For Dietary Iron-Sensing and Its Mutation Leads to Severe Iron Overload.

AUTHOR CONTACT 1:
Silvia Arber
University of Basel, Basel, Switzerland
Phone: 41-61-267-2057; Fax: 41-61-267-2078; E-mail: silvia.arber@unibas.ch

View the PDF of this article at: https://www.the-jci.org/article.php?id=25683

TITLE 2: A Mouse Model of Juvenile Hemochromatosis.

AUTHOR CONTACT 2:
Nancy Andrews
Harvard Medical School, Boston, MA USA
Phone: 617-919-2116; Fax: 617-432-3639; E-mail: nandrews@enders.tch.harvard.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=25049

ACCOMPANYING COMMENTARY:

TITLE: Of mice and men: the iron age

AUTHOR CONTACT:
Sophie Vaulont
Institut Cochin, Paris, France
Phone: 33-144-412-408; Fax: 33-144-412-421; E-mail: vaulont@cochin.inserm.fr

View the PDF of this article at: https://www.the-jci.org/article.php?id=25642

PHYSIOLOGY
What's good for the gut is good for the gallstones

Four years ago, the beta klotho gene in mice and its human homologue were identified. Beta Klotho structurally resembles Klotho, a protein whose deficiency elicits various human ageing-like phenotypes in mice. However, the precise function of beta Klotho has been unknown.

In a new study appearing on August 1 in The Journal of Clinical Investigation, Yo-ichi Nabeshima and colleagues from Kyoto University generated and analyzed beta Klotho-null mice to investigate its function.

The researchers found that beta Klotho is important for cholesterol and bile acid metabolism. Serum cholesterol levels of beta Klotho-null mice were reduced compared with the wild type mice. Moreover, production and excretion of bile acids were dramatically elevated in beta Klotho-null mice.

The expression of two key bile acid synthesis genes, the nuclear receptors regulating these genes, and the liver circulation was intact. However, the negative feedback suppression of one bile acid synthesis gene was significantly impaired. Interestingly, the loss of beta Klotho also provided some benefits to the mice including absence of gallstone formation, and control of body weight and cholesterol levels, suggesting future clinical potential of the beta Klotho system.

In a related commentary, Antonio Moschetta and Steven Kliewer write, "These findings highlight the central role of beta Klotho in bile acid homeostasis and raise the possibility that this protein could be a pharmacological treatment for gallstones."

TITLE: Impaired negative feedback suppression of bile acid synthesis in mice lacking beta Klotho

AUTHOR CONTACT:
Yo-ichi Nabeshima
Kyoto University Graduate School of Medicine, Kyoto Japan
Phone: 8175-753-4422; Fax: 8175-753-4676; E-mail: nabemr@lmls.med.kyoto-u.ac.jp

View the PDF of this article at: https://www.the-jci.org/article.php?id=23076

ACCOMPANYING COMMENTARY:

TITLE: Weaving beta Klotho into bile acid metabolism

AUTHOR CONTACT:
Steven Kliewer
University of Texas Southwestern Medical Center, Dallas, TX USA
Phone: 214-645-6304; Fax: 214-645-6305; E-mail: steven.kliewer@utsouthwestern.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=26046

PHYSIOLOGY
Insulin spares intensive care patients from organ failure and death

It was previously shown, in a large, randomized, controlled trial that controlling blood glucose with insulin reduces the risk of organ failure and death of patients in intensive care. But the underlying mechanisms explaining these clinical benefits remained incompletely understood.

In a new study appearing on August 1 in The Journal of Clinical Investigation, the same group, Greet Van den Berghe and colleagues from Katholieke Universitiet Leuven, show that there is disturbed microcirculation in these patients that is due to endothelial dysfunction which causes inadequate oxygen supply to the cellular systems. The endothelium controls vascular flow and trafficking of important biological molecules. The endothelium of patients with prolonged critical illness is protected by strict blood glucose control with insulin and this may play a major role in the prevention of organ failure and death with this treatment.

This data may open perspectives for novel treatments and for progress in intensive care medicine. In an accompanying commentary, Dandona, et al write, "the results suggest a new paradigm in which glucose and insulin are related not only through their metabolic actions but also through their opposite effects on inflammatory mechanisms."

TITLE: Intensive insulin therapy protects the endothelium of critically ill patients

AUTHOR CONTACT:
Greet Van den Berghe
Katholieke Universiteit Leuven, Leuven, Belgium
Phone: 32-16-344-021; Fax: 32-16-344-015; E-mail: greta.vandenberghe@med.kuleuven.ac.be

View the PDF of this article at: https://www.the-jci.org/article.php?id=25385

ACCOMPANYING COMMENTARY:

TITLE: Insulin infusion in acute illness

AUTHOR CONTACT:
Paresh Dandona
SUNY Buffalo, Buffalo, NY USA
Phone: 716-887-4523; Fax: 716-887-4773; E-mail: pdandona@kaleidahealth.org

View the PDF of this article at: https://www.the-jci.org/article.php?id=26045

CARDIOVASCULAR BIOLOGY
In the debate of atherosclerosis and scavenger receptors, who's right?

Atherosclerosis is a result of the deposition and retention of cholesterol and fats in the arteries. It was believed that scavenger receptors, including SR-A and CD36, bound to cholesterol, leading to its uptake, and that this was a necessary event in atherosclerosis pathogenesis. To validate this idea, several laboratories created mice lacking these receptors and most studies showed that the resulting mice had decreased atherosclerosis and fat accumulation. Thus, it became the dominant hypothesis that cholesterol uptake via SR-A and CD36 were pro-atherogenic.

A new study by Mason Freeman and colleagues at Massachusetts General Hospital, which will appear on August 1 in The Journal of Clinical Investigation, disputes this concept. Here, the authors generated mice that lack CD36, SR-A or both, and measured the impact on atherosclerosis lesion development.

The new results challenge the current dogma of the role of receptor mediated lipid uptake and atherogenesis. The CD36 and SR-A null mice had increased aortic lesion areas, compared to controls. The lesions appeared to be more advanced than those seen in the control mice. These results suggest that scavenger receptor-mediated lipid uptake is not pro-atherosclerotic, as has been reported. In fact, the data presented suggest that scavenger receptor function is protective in atherosclerosis.

In an accompanying commentary, Joseph Witztum discusses potential reasons for the discordant results. He mentions that the reasons why the data are different from previous studies is not quite clear, but that the "data presented by Moore, et al. will cause all of us to stop and reevaluate and to undertake much more experimentation and thought."

TITLE: Loss of lipid uptake via class A scavenger receptors or CD36 pathways does not ameliorate atherosclerosis in hyperlipidemic mice

AUTHOR CONTACT:
Mason Freeman
Massachusetts General Hospital, Boston, MA USA
Phone: 617-726-5906; Fax: 617-726-2879; E-mail: freeman@molbio.mgh.harvard.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=24061

ACCOMPANYING COMMENTARY:

TITLE: You are right too!

AUTHOR CONTACT:
Joseph L. Witztum
University of California San Diego, La Jolla, CA USA
Phone: 858-534-4347; Fax: 858-534-4347; E-mail: jwitztum@ucsd.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=26130

Source: Eurekalert & others

Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
    Published on PsychCentral.com. All rights reserved.

 

 

No one can make you feel inferior without your consent.
~ Eleanor Roosevelt
 
Stumble This Article Print Email
Subscribe to Our Weekly Newsletter

Users Online: 14245
Join Us Now!



 




Find a Therapist
Enter ZIP or postal code