EDITOR'S PICK: Preserving nerve cells in motor neuron disease
A team of researchers, led by Scott Oakes, at the University of California, San Francisco, has identified a way to prevent symptom onset, weight loss, and paralysis and extend survival in a mouse model of amyotrophic lateral sclerosis (ALS; also known as Lou Gehrig's disease), providing a new avenue of research for the development of therapeutics for ALS and other motor neuron diseases.
ALS and other motor neuron diseases are neurological disorders that selectively affect nerve cells that control voluntary muscle activities such as speaking, walking, breathing, swallowing, and general movement of the body. A key feature of these diseases is that the affected nerve cells (which are known as motor neurons) die by a process known as apoptosis. Determining whether this death contributes to disease or occurs after the nerves have stopped functioning is important to establishing whether blocking apoptosis would have therapeutic benefit. In the study, genetically eliminating activation of the mitochondrial apoptotic pathway in a mouse model of ALS was shown to preserve motor neuron viability and function, thereby preventing symptom onset, weight loss, and paralysis and extending survival. The authors therefore suggest that inhibiting activation of the mitochondrial apoptotic pathway might provide a way to preserve motor neurons in individuals with ALS and other motor neuron diseases.
TITLE: Blocking the mitochondrial apoptotic pathway preserves motor neuron viability and function in a mouse model of amyotrophic lateral sclerosis
AUTHOR CONTACT:
Scott A. Oakes
University of California, San Francisco, San Francisco, California, USA.
Phone: 415.476.1777; Fax: 415.514.3165; E-mail: scott.oakes@ucsf.edu.
View this article at: http://www.jci.org/articles/view/42986?key=b51352dad375af860586
HEMATOLOGY: Knocking down obstacles to leukemia therapy
One approach being developed for the treatment of cancer is the infusion of immune cells known as CD8+ T cells into the patient. The transferred CD8+ T cells are specially expanded in culture and selected for being able to target the cancer cells. Although this approach has been effective in some patients, several issues, including poor in vivo survival and function of the transferred cells, have limited further clinical use. However, a team of researchers, led by Philip Greenberg, at the University of Washington, Seattle, has identified a potential way to improve the efficacy of this approach by modeling the therapy in mice with leukemia.
The team found that eliminating the protein Cbl-b in the CD8+ T cells to be transferred increased their therapeutic effects in a mouse model of leukemia. The enhanced therapeutic effects of the transferred CD8+ T cells lacking Cbl-b were a result of their improved survival and enhanced functionality. As knocking down Cbl-b expression in human CD8+ T cell clones had similar in vitro effects, the authors suggest that reducing Cbl-b expression in tumor-specific CD8+ T cells destined for adoptive transfer into patients with cancer might improve their therapeutic efficacy.
TITLE: Abrogating Cbl-b in effector CD8+ T cells improves the efficacy of adoptive therapy of leukemia in mice
AUTHOR CONTACT:
Philip D. Greenberg
Department of Immunology, University of Washington, Seattle, Washington, USA.
Phone: 206.543.8306; Fax: 206.221.2796; E-mail: pgreen@u.washington.edu.
View this article at: http://www.jci.org/articles/view/41991?key=e1ea14c6fcfdb9ddc78c
IMMUNOLOGY: Expanding immune suppressors in vivo
Immune cells known as Tregs have a key role in preventing the immune system from damaging our own bodies. Identifying ways to expand these cells for the treatment of individuals with autoimmune conditions and recipients of transplanted organs is an area of intensive research. Now, Eckhard Podack and colleagues, at the University of Miami Miller School of Medicine, Miami, have determined that stimulating mouse Tregs in vivo via a protein on their cell surface known as TNFRSF25 induces their rapid expansion. Importantly, expanding Tregs in vivo provided protection from subsequent induction of allergic lung inflammation, a mouse model of asthma. The authors therefore believe that their data have may have important implications for the treatment of autoimmune diseases and transplantation as well as chronic infection and cancer, situations in which excessive numbers of Tregs are detrimental.
TITLE: Therapeutic Treg expansion in mice by TNFRSF25 prevents allergic lung inflammation
AUTHOR CONTACT:
Eckhard R. Podack
University of Miami Miller School of Medicine, Miami, Florida, USA.
Phone: 305.243.3033; Fax: 305.243.5522; E-mail: epodack@med.miami.edu.
View this article at: http://www.jci.org/articles/view/42933?key=0f49dca725c6485edef8
DEVELOPMENT: Knocking eye development for Six(3)
The impaired vision and eventual blindness caused by various diseases of the eye are a result of degeneration of the retina — the light-sensitive tissue that lines the inner surface of the eye. It has been suggested that stem cell–based cell replacement therapies might one day be used to treat these conditions. If this is to come to pass, however, we need to better understand normal development of the retina. In this context, a team of researchers, led by Guillermo Oliver, at St. Jude Children's Research Hospital, Memphis, has now identified the protein Six3 as crucial for formation of the mouse neural retina — the portion of the retina that absorbs light, converting the information it provides to something that can be understood by the brain. Mechanistically, Six3 was shown to exert this effect by repressing expression of the Wnt8b gene. The authors hope that their data might help future development of approaches to control the therapeutic generation of neural retina cells.
TITLE: Neuroretina specification in mouse embryos requires Six3-mediated suppression of Wnt8b in the anterior neural plate
AUTHOR CONTACT:
Guillermo Oliver
St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Phone: 901.595.2697; Fax: 901.595.6035; E-mail: guillermo.oliver@stjude.org.
View this article at: http://www.jci.org/articles/view/43219?key=09e6c3c76a9640bf3908
DEVELOPMENT: A Notch(1) in the road to understanding heart valve formation
The most commonly diagnosed congenital heart defects are malformations of the heart valves. Increased understanding of the molecular mechanisms underlying valve formation in the embryo should provide new avenues of research into the origin of cardiac valve defects. New insight into this has now been provided by a team of researchers, led by José Luis de la Pompa, at Centro Nacional de Investigaciones Cardiovasculares, Spain, that studied embryonic heart valve formation in mice.
In the study, the authors generated multiple lines of evidence to support the conclusion that integration of Notch1 signals in endocardial cells and Bmp2 signals in myocardial cells is critical to embryonic heart valve formation in mice. These data suggest that both cell types involved in heart valve formation have an active role, information that provides new insight into the process because it had previously been thought that endocardial cells played a passive role only.
TITLE: Integration of a Notch-dependent mesenchymal gene program and Bmp2-driven cell invasiveness regulates murine cardiac valve formation
AUTHOR CONTACT:
José Luis de la Pompa
Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
Phone: 34.91.4531334; Fax: 34.91.4531304; E-mail: jlpompa@cnic.es.
View this article at: http://www.jci.org/articles/view/42666?key=92920bf5913c6f86296b
CARDIOLOGY: Signaling pathway has distinct effects in two heart cell types
Previous work in animals has suggested that the protein Mst1 might be a target for the treatment of heart failure. But new research in mice, led by Junichi Sadoshima, at the University of Medicine and Dentistry of New Jersey, Newark, now indicates that Mst1 has distinct effects in different cells in the heart such that targeting this protein in all heart cells could be detrimental.
In the study, the protein Rassf1A was found to be an activator of Mst1 in the mouse heart. Consistent with previous work, the Rassf1A/Mst1 pathway promoted heart dysfunction when activated in heart muscle cells. However, when activated in support cells in the heart known as fibroblasts, it provided protection from pressure overload, a model of high blood pressure–induced heart failure. The authors therefore conclude that the consequence of activating the Rassf1A/Mst1 pathway during pressure overload is cell type dependent in the heart and that any therapy targeting this pathway would have to be cell specific.
TITLE: Proapoptotic Rassf1A/Mst1 signaling in cardiac fibroblasts is protective against pressure overload in mice
AUTHOR CONTACT:
Junichi Sadoshima
New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey, USA.
Phone: 973.972.8619; Fax: 973.972.7489; E-mail: sadoshju@umdnj.edu.
View this article at: http://www.jci.org/articles/view/43569?key=343775410582601326d9
CARDIOLOGY: A mitochondrial pore balances energy generation and consumption
New research in mice, led by Jeffery Molkentin, at the University of Cincinnati, Cincinnati, has identified a physiologic function for the mitochondrial permeability transition pore (MPTP), a protein complex with no previously known physiologic function.
Mitochondria are cellular compartments whose main function is to generate energy for the cell. In the study, mice lacking the protein cyclophilin D, which modulates opening of the MPTP, were found to develop more severe heart dysfunction in response to pressure overload, a model of high blood pressure–induced heart failure, than normal mice. Mechanistically, the heart dysfunction was associated with altered MPTP-mediated efflux of calcium ions (Ca2+), with Ca2+ accumulating inside mitochondria. The effects of this lead the authors to suggest that MPTP controls mitochondrial Ca2+ levels to match energy generation by mitochondria with the demand for energy by the cell.
TITLE: Cyclophilin D controls mitochondrial pore–dependent Ca2+ exchange, metabolic flexibility, and propensity for heart failure in mice
AUTHOR CONTACT:
Jeffery D. Molkentin
University of Cincinnati, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Phone: 513.636.3557; Fax: 513.636.5958;
E-mail: jeff.molkentin@cchmc.org.
View this article at: http://www.jci.org/articles/view/43171?key=9d29035e03701e652fad
VIROLOGY: Unraveling how parvovirus B19 causes disease
Parvovirus B19 causes a wide spectrum of human diseases, including fifth disease in children and pure red cell aplasia in patients with a compromised immune system. The mechanisms by which parvovirus B19 causes disease are largely unknown, as there are no cell lines in which the virus can grow and no experimental animals susceptible to infection. But now, Ning Zhi and colleagues, at the National Institutes of Health, Bethesda, have used a recently developed system for culturing parvovirus B19 to identify factors in the infected cells that are exploited by parvovirus B19 to cause disease. Specifically, parvovirus B19 modulates the expression of gene regulatory proteins known as E2Fs to cause the infected cells (human red blood cell progenitors) to stop dividing. These data provide new insight into the mechanisms by which parvovirus B19 causes disease.
TITLE: Human parvovirus B19 causes cell cycle arrest of human erythroid progenitors via deregulation of the E2F family of transcription factors
AUTHOR CONTACT:
Ning Zhi
National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA.
Phone: 301.451.7137; Fax: 301.496.8396; E-mail: zhin@nhlbi.nih.gov.
View this article at: http://www.jci.org/articles/view/41805?key=bbecabf6a68ed773c1c3
Journal
Journal of Clinical Investigation