JCI online early table of contents: April 19, 2010

Altered expression and/or function of the protein BDNF, which promotes nerve cell survival, generation, and function, have been implicated in several neurodegenerative conditions, including Alzheimer disease. Although several properties of BDNF preclude its therapeutic application, it has been suggested that molecules that stimulate the protein to which BDNF binds, TrkB, might have therapeutic potential. Now, a team of researchers, led by Frank Longo, at Stanford University School of Medicine, has developed a two-step screening strategy to identify small molecules that bind to TrkB but not other related proteins and, importantly, demonstrated that one of the compounds they identified prevented nerve cell degradation as efficiently as did BDNF in in vitro models of neurodegenerative conditions. Further, it improved motor learning after traumatic brain injury in rats, leading the authors to suggest that both their two-step approach to drug discovery and the compounds it yielded could prove useful in developing new therapeutics for the treatment of neurodegenerative conditions.

TITLE: Small molecule BDNF mimetics activate TrkB signaling and prevent neuronal degeneration in rodents

AUTHOR CONTACT:
Frank M. Longo
Stanford University School of Medicine, Stanford, California, USA.
Phone: 650.724.3172; Fax: 650.498.4579; E-mail: longo@stanford.edu.

View this article at: http://www.jci.org/articles/view/41356?key=8bab18be763a793f72cd

Anaphylaxis is a severe allergic reaction that is life threatening because it affects the function of multiple organ systems, including the lungs and blood vessels. Its effects on the latter cause them to widen, leading to a dramatic drop in blood pressure, a condition known as anaphylactic shock. New research in mice, performed by Ana Olivera, Juan Rivera, and colleagues, at the National Institutes of Health, Bethesda, has identified a potential new drug target to counteract the widening of blood vessels that is associated with anaphylactic shock.

The proteins SphK1 and SphK2 are involved in generating the soluble molecule S1P, which has effects on blood vessels and the immune system via a family of proteins (S1PR1–S1PR5). In the study, mice lacking SphK2 were found to recover more rapidly from anaphylaxis than normal mice while mice lacking SphK1 recovered poorly. Treating mice lacking SphK1 with S1P dramatically improved their recovery. As these effects of S1P were found to be mediated via S1PR2, the authors suggest that drugs that trigger S1PR2 might counteract the widening of blood vessels associated with anaphylactic shock, thereby promoting recovery.

TITLE: Sphingosine kinase 1 and sphingosine-1-phosphate receptor 2 are vital to recovery from anaphylactic shock in mice

AUTHOR CONTACT:
Ana Olivera
National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland, USA.
Phone: 301.496.7592; Fax: 301.480.1580; E-mail: oliveraa@mail.nih.gov.

Juan Rivera
National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland, USA.
Phone: 301.496.7592; Fax: 301.480.1580; E-mail: juan_rivera@nih.gov.

View this article at: http://www.jci.org/articles/view/40659?key=058b1011a9afa8f70819

The leading cause of death in infants born prematurely is respiratory distress syndrome. It is caused by deficiency in a fat-protein complex known as lung surfactant, which is critical for optimal gas exchange in the lung. LPCAT1 is a recently identified mouse lung protein predicted, based on in vitro assays, to be involved in the generation of surfactant. Now, John Shannon and colleagues, at Cincinnati Children's Hospital Medical Center, have demonstrated that LPCAT1 has a crucial role in the generation of surfactant in vivo in mice and that the activity of this protein must be maximal for the transition from the womb to air breathing. They therefore speculate that decreased LPCAT1 expression, as a result of mutations in the gene responsible for making this protein, might underlie the fatal respiratory distress syndrome observed in a subset of newborn infants.

TITLE: LPCAT1 regulates surfactant phospholipid synthesis and is required for transitioning to air breathing in mice

AUTHOR CONTACT:
John M. Shannon
Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Phone: 513.636.2938; Fax: 513.636.7868; E-mail: John.Shannon@cchmc.org.

View this article at: http://www.jci.org/articles/view/38061?key=6046593af9d76bdabca5

A team of researchers at Chiba University Graduate School of Medicine, Japan, has generated data in mice that suggest that using insulin to treat diabetes could be harmful if the patient has chronic high blood pressure.

Insulin is a hormone that controls the levels of glucose, a key source of energy, in our blood via its effects on the liver, muscle, and fat cells. How insulin affects the heart is not very clear, animal studies suggest that insulin protects the heart from stresses, whereas clinical studies suggest a link between high levels of insulin in the blood and heart failure. The team, led by Issei Komuro, has generated data in mice indicating that while persistent high blood pressure induces liver cell resistance to insulin, it enhances insulin signaling in the heart. This excessive chronic insulin signaling exacerbated heart failure caused by high blood pressure. Importantly, although treating type 1 diabetic mice, which produce no insulin, with insulin stabilized their levels of glucose in the blood, it increased heart failure. Together, these data lead the authors to suggest that insulin treatment could be harmful in the setting of chronic high blood pressure and that maintaining insulin signaling at normal levels is crucial for treating heart failure.

TITLE: Excessive cardiac insulin signaling exacerbates systolic dysfunction induced by pressure overload in rodents

AUTHOR CONTACT:
Issei Komuro
Chiba University Graduate School of Medicine, Chiba, Japan.
Phone: 81.43.226.2097; Fax: 81.43.226.2557; E-mail: komuro-tky@umin.ac.jp.

View this article at: http://www.jci.org/articles/view/40096?key=84e449c5a0d09e8cbf54

Various diarrheal diseases, including the disease seen in some individuals with cystic fibrosis, is caused by disrupted transport of ions across the lining of the large intestine (the colon). A team of researchers, led by Criss Hartzell, at Emory University School of Medicine, Atlanta, has identified a new mechanism by which negatively charged ions are secreted into the colon in mice. Specifically, their data indicate that the protein BEST2 acts as a channel that allows bicarbonate (HCO3–) in the wall of the colon into the cells lining the colon and that it works with a protein that exchanges bicarbonate in the cell for chloride ions (Cl–) in the colon. These data provide new insight into the mechanisms maintaining a healthy colon and suggest that dysregulated BEST2 function might contribute to the symptoms of inflammatory bowel diseases.

TITLE: Bestrophin-2 mediates bicarbonate transport by goblet cells in mouse colon

AUTHOR CONTACT:
H. Criss Hartzell
Emory University School of Medicine, Atlanta, Georgia, USA.
Phone: 404.242.5719; Fax: 404.727.6256; E-mail: Criss.Hartzell@emory.edu.

View this article at: http://www.jci.org/articles/view/41129?key=6f35f1b7028f90e5a07b

The kidney disease crescentic glomerulonephritis rapidly progresses to acute kidney failure and death within months if it is not treated. Even with treatment, many patients progress to end-stage kidney disease and require dialysis and sometimes a kidney transplant. New research in mice, performed by Alan Salama and colleagues, at Hammersmith Hospital, United Kingdom, has identified a potential new drug target for the treatment of crescentic glomerulonephritis.

In the study, mice lacking the mannose receptor protein were found to be protected from crescentic glomerulonephritis. This protection was associated with decreased kidney damage mediated by cells known as macrophages and mesangial cells. Further, macrophages lacking the mannose receptor actually became antiinflammatory in the kidney after they interacted with mesangial cells. The authors therefore suggest that targeting the mannose receptor might provide a new approach to treating crescentic glomerulonephritis. Importantly, this approach would not have the wide-ranging immunosuppressive effects that many current therapies have.

TITLE: Mannose receptor interacts with Fc receptors and is critical for the development of crescentic glomerulonephritis in mice

AUTHOR CONTACT:
Alan D. Salama
Imperial College London, Hammersmith Hospital, London, United Kingdom.
Phone: 44.208.383.3980; Fax: 44.208.383.3980; E-mail: A.salama@imperial.ac.uk.

View this article at: http://www.jci.org/articles/view/41560?key=d53c2a91c86f55cbfa8c

Individuals with the rare human genetic disease Fanconi anemia have an increased incidence of cancer. In many individuals, disease is caused by mutations in any one of 13 known genes (including FANCL) that generate proteins that function in one common signaling pathway that is known as the FA pathway. Whether this pathway has a role in human cancers in individuals who do not have Fanconi anemia has not been clearly determined. But now, Peiwen Fei and colleagues, at the Mayo Clinic, Rochester, have identified a new form of the protein FANCL, which they named FAVL, that dysregulates the FA pathway in non-FA human tumor cells and acts as a tumor-promoting factor. The authors therefore conclude that impairment of the FA pathway could contribute to the development of cancer in individuals who do not have Fanconia anemia.

TITLE: FAVL elevation in human tumors disrupts Fanconi anemia pathway signaling and promotes genomic instability and tumor growth

AUTHOR CONTACT:
Peiwen Fei
Mayo Clinic, Rochester, Minnesota, USA.
Phone: 507.284.1733; Fax: 507.284.1678; E-mail: fei.peiwen@mayo.edu.

View this article at: http://www.jci.org/articles/view/40908?key=17b397e487840dfd626d

Autoimmune disease arises when an individual's immune system attacks other cells in the body. Individuals who develop an autoimmune disease often express certain forms of proteins known as MHC class II molecules. For example, expression of the MHC class II molecule HLA-DR4 is associated with rheumatoid arthritis. Many of the MHC class II molecules linked to type 1 diabetes, including HLA-DQ8 in humans and I-Ag7 in mice, lack a specific protein building block (aspartic acid) at a given point in the full protein (beta-57). Exactly why this is linked to type 1 diabetes has been unclear. However, a team of researchers, led by Luc Teyton and Ian Wilson, at The Scripps Research Institute, La Jolla, has now determined that the presence I-Ag7 in mice leads to the development of immune cells known as T cells that have the potential to bind with high affinity to cells expressing the MHC class II molecule, an event that under certain circumstances triggers them to attack the body causing type 1 diabetes.

TITLE: The diabetogenic mouse MHC class II molecule I-Ag7 is endowed with a switch that modulates TCR affinity

AUTHOR CONTACT:
Luc Teyton
The Scripps Research Institute, La Jolla, California, USA.
Phone: 858.784.2728; Fax: 858.784.8166; E-mail: lteyton@scripps.edu.

Ian A. Wilson
The Scripps Research Institute, La Jolla, California, USA.
Phone: 858.784.9706; Fax: 858.784.2980; E-mail: wilson@scripps.edu.

View this article at: http://www.jci.org/articles/view/41502?key=5ae65f4c82e501fbfb55